Yong Lin

Publications (44)233.81 Total impact

• Article: RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species.

  Qiong Wang, Wenshu Chen, Xiuling Xu, Bilan Li, Weiyang He, Mabel T Padilla, Jun-Ho Jang, Toru Nyunoya, Shantu Amin, Xia Wang, Yong Lin
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  ABSTRACT: Cell survival signaling is important for the malignant phenotypes of cancer cells. Although the role of receptor-interacting protein 1 (RIP1) in cell survival signaling is well documented, whether RIP1 is directly involved in cancer development has never been studied. In this report, we found that RIP1 expression is substantially increased in human non-small cell lung cancer (NSCLC) and mouse lung tumor tissues. RIP1 expression was remarkably increased in cigarette smoke-exposed mouse lung. In human bronchial epithelial cells (HBECs) RIP1 was significantly induced by cigarette smoke extract (CSE) or benzo[a]pyrene diol epoxide (BPDE), the active form of the tobacco-specific carcinogen benzo (a) pyrene (BaP). In RIP1 knockdown HBECs, BPDE-induced cytotoxicity was significantly increased, which was associated with induction of cellular reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs) including JNK, ERK and p38. Scavenging ROS suppressed BPDE-induced MAPK activation and inhibiting ROS or MAPKs substantially blocked BPDE-induced cytotoxicity, suggesting ROS-mediated MAPK activation is involved in BPDE-induced cell death. The ROS-reducing enzyme catalase is destabilized in an ERK- and JNK-dependent manner in RIP1 knockdown HBECs and application of catalase effectively blocked BPDE-induced ROS accumulation and cytotoxicity. Importantly, BPDE-induced transformation of HBECs was significantly reduced when RIP1 expression was suppressed. Altogether, these results strongly suggest an oncogenic role for RIP1, which promotes malignant transformation through protecting DNA-damaged cells against carcinogen-induced cytotoxicity associated with excessive ROS production.
  Carcinogenesis 04/2013; · 5.70 Impact Factor
• Article: Wogonin enhances antitumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated downregulation of cFLIP(L) and IAP proteins.

  Lan Yang, Qiong Wang, Daoxia Li, Yuqiong Zhou, Xuelian Zheng, Hong Sun, Jiaqi Yan, Lin Zhang, Yong Lin, Xia Wang
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  ABSTRACT: Combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with other agents is a promising strategy to overcome TRAIL resistance in malignant cells. Wogonin, a flavonoid originated from Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. However, whether wogonin enhances TRAIL's antitumor activity in vivo has never been studied. In this study, the effect of combination of TRAIL and wogonin was tested in a non-small-cell lung cancer xenografted tumor model in nude mice. Consistent with the in vitro study showing that wogonin sensitized A549 cells to TRAIL-induced apoptosis, wogonin greatly enhanced TRAIL-induced suppression of tumor growth, accompanied with increased apoptosis in tumor tissues as determined by TUNEL assay. The expression levels of antiapoptotic proteins including long form of cellular FLICE-like inhibitory protein (cFLIP(L)), X-linked inhibitor of apoptosis protein (XIAP), and cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) were markedly reduced in both cultured cells and xenografted tumor tissues after co-treatment with wogonin and TRAIL. The down-regulation of these antiapoptotic proteins was likely mediated by proteasomal degradation that involved intracellular reactive oxygen species (ROS), because wogonin robustly induced ROS accumulation and ROS scavengers butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins in cells co-treated with wogonin and TRAIL. These results show for the first time that wogonin enhances TRAIL's antitumor activity in vivo, suggesting this strategy has an application potential for clinical anticancer therapy.
  Apoptosis 01/2013; · 4.07 Impact Factor
• Article: Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.

  Shuguang Leng, Maria A Picchi, Yushi Liu, Cindy L Thomas, Derall G Willis, Amanda M Bernauer, Teara G Carr, Mabel T Padilla, Younghun Han, Christopher I Amos, Yong Lin, Christine A Stidley, Frank D Gilliland, Marty R Jacobson, Steven A Belinsky
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  ABSTRACT: Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks (DSBs) induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P=0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (Odds Ratio = 1.69, P = 8.2×10(-5)) and greater survival in SCC cases (Hazard Ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggested that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.
  Carcinogenesis 01/2013; · 5.70 Impact Factor
• Article: Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation.

  Weiyang He, Qiong Wang, Jennings Xu, Xiuling Xu, Mabel T Padilla, Guosheng Ren, Xin Gou, Yong Lin
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  ABSTRACT: Although it is known that tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) induces autophagy, the mechanism by which autophagy is activated by TNFSF10 is still elusive. In this report, we show evidence that TRAF2- and RIPK1-mediated MAPK8/JNK activation is required for TNFSF10-induced cytoprotective autophagy. TNFSF10 activated autophagy rapidly in cancer cell lines derived from lung, bladder and prostate tumors. Blocking autophagy with either pharmacological inhibitors or siRNAs targeting the key autophagy factors BECN1/Beclin 1 or ATG7 effectively increased TNFSF10-induced apoptotic cytotoxicity, substantiating a cytoprotective role for TNFSF10-induced autophagy. Blocking MAPK8 but not NFκB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TNFSF10-induced autophagy. In addition, blocking MAPK8 effectively inhibited degradation of BCL2L1/Bcl-xL and reduction of the autophagy-suppressing BCL2L1-BECN1complex. Knockdown of TRAF2 or RIPK1 effectively suppressed TNFSF10-induced MAPK8 activation and autophagy. Furthermore, suppressing autophagy inhibited expression of antiapoptosis factors BIRC2/cIAP1, BIRC3/cIAP2, XIAP and CFLAR/c-FLIP and increased the formation of TNFSF10-induced death-inducing signaling complex (DISC). These results reveal a critical role for the MAPK8 activation pathway through TRAF2 and RIPK1 for TNFSF10-induced autophagy that blunts apoptosis in cancer cells. Thus, suppression of MAPK8-mediated autophagy could be utilized for sensitizing cancer cells to therapy with TNFSF10.
  Autophagy 10/2012; 8(12). · 7.45 Impact Factor
• Article: Concurrent blockade of NF-κB and Akt pathways potentiates cisplatin's antitumor activity in vivo.

  Hong Sun, Xuelian Zheng, Qiong Wang, Jiaqi Yan, Daoxia Li, Yuqiong Zhou, Yong Lin, Lin Zhang, Xia Wang
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  ABSTRACT: Nuclear factor-κB (NF-κB) and Akt are two major cell-survival pathways that are often constitutively activated in cancer cells. It has been established that these two pathways contribute substantially toward the chemoresistance of cancer cells. Our previous study has demonstrated that NF-κB and Akt cooperatively blunt cytotoxicity induced by cisplatin or etopside in different types of cancer cells in vitro, indicating that the concurrent blocking of these pathways may effectively improve the anticancer efficacy of anticancer therapeutics. In this study, we further investigated the effect of concurrent blockade of NF-κB and Akt on the anticancer activity of cisplatin in vivo in a xenograft tumor model. The NF-κB and Akt pathways in the A549 lung cancer cells were blocked individually or concurrently by the stable transfection of plasmids expressing short hairpin RNAs that target Akt1 and IκB kinase β. The resultant cells with concurrent NF-κB and Akt blockade were significantly more sensitive to cisplatin-induced cell death in vitro. Consistently, tumors derived from cells with the concurrent blockade of NF-κB and Akt were much more sensitive to cisplatin compared with those derived from cells with individual blockage of NF-κB or Akt in a nude mouse xenograft tumor model. Apoptosis was significantly enhanced in the double pathway-suppressed and cisplatin-treated tumors. These results show for the first time that the concurrent blockage of the NF-κB and Akt pathways cooperatively potentiates the antitumor activity of cisplatin in vivo, indicating that this strategy may be potentially useful for clinical anticancer therapy.
  Anti-cancer drugs 07/2012; 23(10):1039-46. · 2.23 Impact Factor
• Article: Wogonin potentiates cisplatin-induced cancer cell apoptosis through accumulation of intracellular reactive oxygen species.

  Fan He, Qiong Wang, Xue-Lian Zheng, Jia-Qi Yan, Lan Yang, Hong Sun, Li-Na Hu, Yong Lin, Xia Wang
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  ABSTRACT: Chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic. The combination of cisplatin with other agents has been recognized as a promising strategy to overcome cisplatin resistance. Previous studies have shown that wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid isolated from the root of the medicinal herb Scutellaria baicalensis Georgi, sensitizes cancer cells to chemotheraputics such as etoposide, adriamycin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TNF. However, the effect of wogonin on cisplatin-induced cytotoxicity has not been previously reported. In this study, the non-small cell lung cancer cell line A549 and the cervical cancer cell line HeLa were treated with wogonin or cisplatin individually or in combination. It was found for the first time that wogonin is able to sensitize cisplatin-induced apoptosis in both A549 cells and HeLa cells as indicated by the potentiation of activation of caspase-3, and cleavage of the caspase-3 substrate PARP in wogonin and cisplatin co-treated cells. Importantly, wogonin robustly induced H2O2 accumulation in these cells, which substantially contributes to the sensitization of cisplatin cytotoxicity by wogonin, as two reactive oxygen species scavengers, butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC), significantly suppressed the potentiated cytotoxicity caused by wogonin and cisplatin co-treatment. The results from this study provide important new evidence supporting the potential use of wogonin as a cisplatin sensitizer for cancer therapy.
  Oncology Reports 05/2012; 28(2):601-5. · 1.84 Impact Factor
• Article: Low-dose gamma-irradiation inhibits IL-6 secretion from human lung fibroblasts that promotes bronchial epithelial cell transformation by cigarette-smoke carcinogen.

  Wenshu Chen, Xiuling Xu, Lang Bai, Mabel T Padilla, Katherine M Gott, Shuguang Leng, Carmen S Tellez, Julie A Wilder, Steven A Belinsky, Bobby R Scott, Yong Lin
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  ABSTRACT: Despite decades of research in defining the health effects of low-dose (<100 mGy) ionizing photon radiation (LDR), the relationship between LDR and human cancer risk remains elusive. Because chemical carcinogens modify the tumor microenvironment, which is critical for cancer development, we investigated the role and mechanism of LDR in modulating the response of stromal cells to chemical carcinogen-induced lung cancer development. Secretion of proinflammatory cytokines such as interleukin-6 (IL-6), CXCL1 and CXCL5 from human lung fibroblasts was induced by cigarette-smoke carcinogen benzo[a]pyrene diol epoxide (BPDE), which was inhibited by a single dose of LDR. The activation of NF-κB, which is important for BPDE-induced IL-6 secretion, was also effectively suppressed by LDR. In addition, conditioned media from BPDE-treated fibroblasts activated STAT3 in the immortalized normal human bronchial epithelial cell line Beas-2B, which was blocked with an IL-6 neutralizing antibody. Conditioned medium from LDR-primed and BPDE-treated fibroblast showed diminished capacity in activating STAT3. Furthermore, IL-6 enhanced BPDE-induced Beas-2B cell transformation in vitro. These results suggest that LDR inhibits cigarette smoke-induced lung carcinogenesis by suppressing secretion of cytokines such as IL-6 from fibroblasts in lung tumor-prone microenvironment.
  Carcinogenesis 05/2012; 33(7):1368-74. · 5.70 Impact Factor
• Article: Critical role of CD40-mediated autocrine tumor necrosis factor-alpha in potentiation of cisplatin-induced cytotoxicity in cancer cells.

  Hong Sun, Ying-Jia Zhong, Xue-Lian Zheng, Qiong Wang, Lan Yang, Fang Shi, Jia-Qi Yan, Fan He, Lin-Chuan Liao, Yong Lin, Lin Zhang, Xia Wang
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  ABSTRACT: Activation of CD40, a member of the tumor necrosis factor receptor (TNF-R) family, results in growth inhibition or apoptosis in some tumor cells, making CD40 a potential antitumor therapeutic target. Although it is known that CD40 is able to induce tumor necrosis factor-alpha (TNF-α) secretion and potentiate cisplatin's anticancer activity, whether TNF-α induction is involved in sensitizing cisplatin by CD40 has not been addressed. In this report, we provide evidence substantiating an important role of autocrine TNF-α in potentiation of cisplatin-induced apoptosis by recombinant soluble CD40 ligand (rsCD40L) in different human cancer cell lines. Activation of CD40 by rsCD40L induces two phases of autocrine TNF-α: the rapid early phase involving p38 MAP kinase and the robust and persistent late phase through enhanced tnf-α gene transcription. Blocking TNF-α with either a specific TNFR1 siRNA or a neutralizing anti-TNF-α antibody dramatically attenuated the potentiation effect of rsCD40L on cisplatin-induced cancer cell death. These results reveal an important role of TNF-α induction in CD40's chemosensitization activity and suggest that modulating TNF-α autocrine from cancer cells is an effective option for increasing the anticancer value of chemotherapeutics such as cisplatin.
  Cancer Science 02/2012; 103(2):197-202. · 3.33 Impact Factor
• Source

  Available from: Xiuling Xu

  Article: MUC1 contributes to BPDE-induced human bronchial epithelial cell transformation through facilitating EGFR activation.

  Xiuling Xu, Lang Bai, Wenshu Chen, Mabel T Padilla, Yushi Liu, Kwang Chul Kim, Steven A Belinsky, Yong Lin
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  ABSTRACT: Although it is well known that epidermal growth factor receptor (EGFR) is involved in lung cancer progression, whether EGFR contributes to lung epithelial cell transformation is less clear. Mucin 1 (MUC1 in human and Muc1 in animals), a glycoprotein component of airway mucus, is overexpressed in lung tumors; however, its role and underlying mechanisms in early stage lung carcinogenesis is still elusive. This study provides strong evidence demonstrating that EGFR and MUC1 are involved in bronchial epithelial cell transformation. Knockdown of MUC1 expression significantly reduced transformation of immortalized human bronchial epithelial cells induced by benzo[a]pyrene diol epoxide (BPDE), the active form of the cigarette smoke (CS) carcinogen benzo(a)pyrene (BaP)s. BPDE exposure robustly activated a pathway consisting of EGFR, Akt and ERK, and blocking this pathway significantly increased BPDE-induced cell death and inhibited cell transformation. Suppression of MUC1 expression resulted in EGFR destabilization and inhibition of the BPDE-induced activation of Akt and ERK and increase of cytotoxicity. These results strongly suggest an important role for EGFR in BPDE-induced transformation, and substantiate that MUC1 is involved in lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR-mediated cell survival pathway that facilitates cell transformation.
  PLoS ONE 01/2012; 7(3):e33846. · 4.09 Impact Factor
• Article: Luteolin enhances TNF-related apoptosis-inducing ligand's anticancer activity in a lung cancer xenograft mouse model.

  Jiaqi Yan, Qiong Wang, Xuelian Zheng, Hong Sun, Yuqiong Zhou, Daoxia Li, Yong Lin, Xia Wang
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  ABSTRACT: Sensitization of cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by luteolin has been suggested by in vitro studies. However, no in vivo experiment has been reported to validate the potentiation effect of luteolin on TRAIL's anticancer activity. In this report, we first confirmed that luteolin potentiates TRAIL-induced cytotoxicity in A549 cells and HeLa cells in association with increased activation of apoptosis. Then we performed an in vivo experiment with a non-small cell lung cancer xenograft mouse model, which showed for the first time that the in vivo anticancer activity of TRAIL was greatly enhanced by luteolin. Compared with that in untreated control or treatment with TRAIL or luteolin alone, inhibition of tumor growth and apoptotic cell death in xenograft tumors were significantly increased in animals receiving combination treatment with TRAIL and luteolin. Data from this study thus provide strong in vivo evidence supporting that luteolin is a potential sensitizer for TRAIL in anticancer therapy.
  Biochemical and Biophysical Research Communications 12/2011; 417(2):842-6. · 2.48 Impact Factor
• Article: Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms.

  Ying-jia Zhong, Fang Shi, Xue-lian Zheng, Qiong Wang, Lan Yang, Hong Sun, Fan He, Lin Zhang, Yong Lin, Yong Qin, Lin-chuan Liao, Xia Wang
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  ABSTRACT: To investigate the anticancer effect of crocetin, a major ingredient in saffron, and its underlying mechanisms. Cervical cancer cell line HeLa, non-small cell lung cancer cell line A549 and ovarian cancer cell line SKOV3 were treated with crocetin alone or in combination with vincristine. Cell proliferation was examined using MTT assay. Cell cycle distribution and sub-G(1) fraction were analyzed using flow cytometric analysis after propidium iodide staining. Apoptosis was detected using the Annexin V-FITC Apoptosis Detection Kit with flow cytometry. Cell death was measured based on the release of lactate dehydrogenase (LDH). The expression levels of p53 and p21(WAF1/Cip1) as well as caspase activation were examined using Western blot analysis. Treatment of the 3 types of cancer cells with crocetin (60-240 μmol/L) for 48 h significantly inhibited their proliferation in a concentration-dependent manner. Crocetin (240 μmol/L) significantly induced cell cycle arrest through p53-dependent and -independent mechanisms accompanied with p21(WAF1/Cip1) induction. Crocetin (120-240 μmol/L) caused cytotoxicity in the 3 types of cancer cells by enhancing apoptosis in a time-dependent manner. In the 3 types of cancer cells, crocetin (60 μmol/L) significantly enhanced the cytotoxicity induced by vincristine (1 μmol/L). Furthermore, this synergistic effect was also detected in the vincristine-resistant breast cancer cell line MCF-7/VCR. Ccrocetin is a potential anticancer agent, which may be used as a chemotherapeutic drug or as a chemosensitizer for vincristine.
  Acta Pharmacologica Sinica 12/2011; 32(12):1529-36. · 1.95 Impact Factor
• Article: Epidermal growth factor receptor-mediated tissue transglutaminase overexpression couples acquired tumor necrosis factor-related apoptosis-inducing ligand resistance and migration through c-FLIP and MMP-9 proteins in lung cancer cells.

  Zi Li, Xiuling Xu, Lang Bai, Wenshu Chen, Yong Lin
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  ABSTRACT: Acquired chemoresistance not only blunts anticancer therapy but may also promote cancer cell migration and metastasis. Our previous studies have revealed that acquired tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in lung cancer cells is associated with Akt-mediated stabilization of cellular caspase 8 and Fas-associated death domain (FADD)-like apoptosis regulator-like inhibitory protein (c-FLIP) and myeloid cell leukemia 1 (Mcl-1). In this report, we show that cells with acquired TRAIL resistance have significantly increased capacities in migration and invasion. By gene expression screening, tissue transglutaminase (TGM2) was identified as one of the genes with the highest expression increase in TRAIL-resistant cells. Suppressing TGM2 dramatically alleviated TRAIL resistance and cell migration, suggesting that TGM2 contributes to these two phenotypes in TRAIL-resistant cells. TGM2-mediated TRAIL resistance is likely through c-FLIP because TGM2 suppression significantly reduced c-FLIP but not Mcl-1 expression. The expression of matrix metalloproteinase 9 (MMP-9) was suppressed when TGM2 was inhibited, suggesting that TGM2 potentiates cell migration through up-regulating MMP-9 expression. We found that EGF receptor (EGFR) was highly active in the TRAIL-resistant cells, and suppression of EGFR dramatically reduced TGM2 expression. We further determined JNK and ERK, but not Akt and NF-κB, are responsible for EGFR-mediated TGM2 expression. These results identify a novel pathway that involves EGFR, MAPK (JNK and ERK), and TGM2 for acquired TRAIL resistance and cell migration in lung cancer cells. Because TGM2 couples TRAIL resistance and cell migration, it could be a molecular target for circumventing acquired chemoresistance and metastasis in lung cancer.
  Journal of Biological Chemistry 06/2011; 286(24):21164-72. · 4.77 Impact Factor
• Article: A HIF-1 target, ATIA, protects cells from apoptosis by modulating the mitochondrial thioredoxin, TRX2.

  Swati Choksi, Yong Lin, Yelena Pobezinskaya, Li Chen, Chung Park, Michael Morgan, Tao Li, Siriporn Jitkaew, Xiumei Cao, You-Sun Kim, Hong-Sug Kim, Peter Levitt, Grace Shih, Michael Birre, Chu-Xia Deng, Zheng-Gang Liu
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  ABSTRACT: The regulation of apoptosis is critical for controlling tissue homeostasis and preventing tumor formation and growth. Reactive oxygen species (ROS) generation plays a key role in such regulation. Here, we describe a HIF-1 target, Vasn/ATIA (anti-TNFα-induced apoptosis), which protects cells against TNFα- and hypoxia-induced apoptosis. Through the generation of ATIA knockout mice, we show that ATIA protects cells from apoptosis through regulating the function of the mitochondrial antioxidant, thioredoxin-2, and ROS generation. ATIA is highly expressed in human glioblastoma, and ATIA knockdown in glioblastoma cells renders them sensitive to hypoxia-induced apoptosis. Therefore, ATIA is not only a HIF-1 target that regulates mitochondrial redox pathways but also a potentially diagnostic marker and therapeutic target in human glioblastoma.
  Molecular cell 06/2011; 42(5):597-609. · 14.61 Impact Factor
• Article: EGFR-mediated tissue transglutaminase overexpression couples acquired TRAIL-resistance and migration through c-FLIP and MMP-9 in lung cancer cells

  Zi Li, Xiuling Xu, Lang Bai, Wenshu Chen, Yong Lin
  [show abstract] [hide abstract]
  ABSTRACT: Acquired chemoresistance not only blunts anticancer therapy, but may also promote cancer cell migration and metastasis. Our previous studies have revealed that acquired tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in lung cancer cells is associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and myeloid cell leukemia 1 (Mcl-1). In this report, we show that cells with acquired TRAIL-resistance have significantly increased capacities in migration and invasion. By gene expression screening, tissue transglutaminase (TGM2) was identified as one of the genes with the highest expression increase in TRAIL-resistant cells. Suppressing TGM2 dramatically alleviated TRAIL-resistance and cell migration, suggesting TGM2 contributes to these two phenotypes in TRAIL-resistant cells. TGM2-mediated TRAIL-resistance is likely through c-FLIP because TGM2 suppression significantly reduced c-FLIP but not Mcl-1 expression. The expression of matrix metalloproteinase 9 (MMP-9) was suppressed when TGM2 was inhibited, suggesting that TGM2 potentiates cell migration through upregulating MMP-9 expression. We found that epidermal growth factor receptor (EGFR) was highly active in the TRAIL-resistant cells and suppression of EGFR dramatically reduced TGM2 expression. We further determined JNK and ERK, but not Akt and NF-κB, are responsible for EGFR-mediated TGM2 expression. These results identify a novel pathway that involves EGFR, MAPK (JNK and ERK) and TGM2 for acquired TRAIL-resistance and cell migration in lung cancer cells. Because TGM2 couples TRAIL-resistance and cell migration, it could be a molecular target for circumventing acquired chemoresistance and metastasis in lung cancer.
  Journal of Biological Chemistry 04/2011; · 4.77 Impact Factor
• Article: TNFα induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2.

  Joo-Young Kim, Michael Morgan, Dong-Gun Kim, Ju-Yeon Lee, Lang Bai, Yong Lin, Zheng-Gang Liu, You-Sun Kim
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  ABSTRACT: The current paradigm of noncanonical NF-κB signaling suggests that the loss of TRAF2, TRAF3 or cIAP1 and cIAP2 leads to stabilization of NF-κB-inducing kinase (NIK) to activate the noncanonical pathway. Although a crucial role of RIP1 in the TNFα-induced canonical NF-κB pathway has been well established, its involvement in noncanonical activation of NF-κB through the TNFR1 receptor, is unknown. Here we show that TNFα is capable of activating the noncanonical NF-κB pathway, but that activation of this pathway is negatively regulated by RIP1. In the absence of RIP1, TNFR1 stimulation leads to activation of the noncanonical NF-κB pathway through TRAF2 degradation, leading to NIK stabilization, IKKα phosphorylation and the processing of p100 to generate p52. Thus although RIP1(-/-) mouse embryonic fibroblasts are sensitive at early time points to cell death induced by TNFα, probably as a result of lack of canonical NF-κB activation, the late activation of the noncanonical NF-κB pathway protects the remaining cells from further cell death. The TNFR1-dependent noncanonical NF-κB activation in RIP1(-/-) cells suggests that there is functional interplay between the two NF-κB pathways during TNFR1 signaling, which might regulate the number and kinds of NF-κB transcription factors and thus finely control NF-κB-dependent gene transcription.
  Journal of Cell Science 02/2011; 124(Pt 4):647-56. · 6.11 Impact Factor
• Article: NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target.

  Wenshu Chen, Zi Li, Lang Bai, Yong Lin
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  ABSTRACT: Lung cancer ranks as the first malignant tumor killer worldwide. Despite the knowledge that carcinogens from tobacco smoke and the environment constitute the main causes of lung cancer, the mechanisms for lung carcinogenesis are still elusive. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to cancer development. As a major cell survival signal, nuclear factor-kappaB (NF-kappaB) is involved in multiple steps in carcinogenesis and in cancer cell's resistance to chemo- and radio-therapy. Recent studies with animal models and cell culture systems have established the links between NF-kappaB and lung carcinogenesis, highlighting the significance of targeting NF-kappa signaling pathway for lung cancer treatment and chemoprevention. In this review, we summarize progresses in understanding the NF-kappaB pathway in lung cancer development as well as in modulating NF-kappaB for lung cancer prevention and therapy.
  Frontiers in Bioscience 01/2011; 16:1172-85. · 3.52 Impact Factor
• Article: Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death.

  Lang Bai, Shanling Xu, Wenshu Chen, Zi Li, Xia Wang, Hong Tang, Yong Lin
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  ABSTRACT: NF-κB and Akt are two main cell survival pathways that attenuate the anticancer efficacy of therapeutics. Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-α autocrine to kill cancer cells. However, SMC3 also induces a cell survival signal through NF-κB activation. In this report, we further found that SMC3 potently activates Akt, which inhibits SMC3-induced cancer cell death. Strikingly, concurrent blocking NF-κB and Akt resulted in a significantly potentiated cytotoxicity. Because heat shock protein 90 (Hsp90) plays an important role in maintaining the integrity of both the NF-κB and Akt pathways in cancer cells, we examined if suppression of Hsp90 is able to potentiate SMC3-induced cancer cell death. The results show that targeting Hsp90 does not interfere with SMC3-induced c-IAP1 degradation and TNF-α autocrine, the key processes for SMC3-induced cancer cell apoptosis. However, Hsp90 inhibitors effectively blocked SMC3-induced NF-κB activation through degradation of RIP1 and IKKβ, two key components of the NF-κB activation pathway, and reduced both the constitutive and SMC3-induced Akt activity through degradation of the Akt protein. Consistently, with the co-treatment of SMC3 and Hsp90 inhibitors, apoptosis was markedly sensitized and a synergistic cytotoxicity was observed. The results suggest that concurrent targeting c-IAP1 and Hsp90 by combination of SMC3 and Hsp90 inhibitors is an effective approach for improving the anticancer value of SMC3.
  Apoptosis 01/2011; 16(1):45-54. · 4.07 Impact Factor
• Article: Catalase suppression-mediated H(2)O(2) accumulation in cancer cells by wogonin effectively blocks tumor necrosis factor-induced NF-κB activation and sensitizes apoptosis.

  Lan Yang, Xue L Zheng, Hong Sun, Ying J Zhong, Qiong Wang, Hai N He, Xun W Shi, Bing Zhou, Jin K Li, Yong Lin, Lin Zhang, Xia Wang
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  ABSTRACT: Tremendous effort has been made to improve the anticancer value of tumor necrosis factor (TNF). In this study, we show that wogonin, a flavonoid isolated from Huang-Qin (Scutellaria baicalensis), synergistically sensitizes cancer cells derived from the cervix, ovary and lung to TNF-induced apoptosis, which was associated with inhibition of catalase activity and an increase of cellular hydrogen peroxide (H(2)O(2)). Wogonin-induced reactive oxygen species block TNF-induced NF-κB activation through inhibiting phosphorylation on the NF-κB p65 subunit and consequently the DNA binding of NF-κB. In addition, wogonin suppressed the expression of the antiapoptotic factor c-FLIP, which is accompanied with potentiation of TNF-induced caspase 8 activation that initiates apoptosis. Importantly, wogonin did not sensitize normal bronchial epithelial cells to TNF-induced cell death, which was associated with the defect in induction of H(2)O(2). Thus, wogonin specifically sensitizes cancer cells to TNF-induced cytotoxicity through H(2)O(2)-mediated NF-κB suppression and apoptosis activation. Our data provide important insights into the molecular mechanism underlying wogonin's anticancer activity, and suggest this common flavonoid could be used as a TNF adjuvant for cancer therapy.
  Cancer Science 01/2011; 102(4):870-6. · 3.33 Impact Factor
• Article: Concurrent blockade of the NF-kappaB and Akt pathways potently sensitizes cancer cells to chemotherapeutic-induced cytotoxicity.

  Hai-Ning He, Xia Wang, Xue-Lian Zheng, Hong Sun, Xun-Wei Shi, Ying-Jia Zhong, Bo Huang, Lan Yang, Jin-Ke Li, Lin-Chuan Liao, Lin Zhang, Li-Na Hu, Yong Lin
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  ABSTRACT: Nuclear factor-kappaB (NF-kappaB) and Akt are two major cell survival pathways that are often constitutively activated and can be further stimulated by chemotherpeutics in cancer cells. Although individually targeting the NF-kappaB or Akt has been reported to sensitize caner therapy, the effectiveness of concurrent blocking these two pathways for chemosensitizing of cancer cells to genotoxic therapeutics has not been investigated. In the present study, we investigate the activation of the NF-kappaB and Akt pathways by two frontline anticancer drugs cisplatin and etopside in a variety of cancer cell lines. The effects of blocking these two survival pathways individually or concurrently on cisplatin- or etopside-induced cytotoxicity were detected. The results show that cisplatin and etopside activate both NF-kappaB and Akt in cancer cells. Blockade of either of these pathways with chemical inhibitors or siRNA moderately sensitized cancer cells to cisplatin- or etopside-induced cytotoxicity. Strikingly, much more effective potentiation of cytotoxicity to these anticancer drugs was achieved when NF-kappaB and Akt were concurrently blocked. These data suggest that NF-kappaB and Akt cooperatively attenuate therapeutic-induced cytotoxicity and concurrently blocking these pathways is an effective strategy for improving the anticancer efficacy of therapeutics.
  Cancer letters 03/2010; 295(1):38-43. · 4.86 Impact Factor
• Article: The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy.

  Yong Lin, Lang Bai, Wenjie Chen, Shanling Xu
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  ABSTRACT: Nuclear factor kappa B (NF-kappaB) is activated by a variety of cancer-promoting agents. The reciprocal activation between NF-kappaB and inflammatory cytokines makes NF-kappaB important for inflammation-associated cancer development. Both the constitutive and anticancer therapeutic-induced NF-kappaB activation blunts the anticancer activities of the therapy. Elucidating the roles of NF-kappaB in cancer facilitates developing approaches for cancer prevention and therapy. By searching PubMed, we summarize the progress of studies on NF-kappaB in carcinogenesis and cancer cells' drug resistance in recent 10 years. The mechanisms by which NF-kappaB activation pathways are activated; the roles and mechanisms of NF-kappaB in cell survival and proliferation, and in carcinogenesis and cancer cells' response to therapy; recent development of NF-kappaB-modulating means and their application in cancer prevention and therapy. NF-kappaB is involved in cancer development, modulating NF-kappaB activation pathways has important implications in cancer prevention and therapy. Due to the complexity of NF-kappaB roles in different cancers, careful evaluation of NF-kappaB's in each cancer type is crucial in this regard. More cancer cell-specific NF-kappaB inhibiting means are desired for improving anticancer efficacy and reducing systemic toxicity.
  Expert opinion on therapeutic targets 01/2010; 14(1):45-55. · 3.72 Impact Factor