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ABSTRACT: Natural chalcones have been proved to inhibit cancer cells with therapeutic potential, but the underlying molecular mechanism is still largely unexplored. Here, we identified a novel chalcone, 2'-hydroxy-4',5'-dimethoxychalcone (HDMC) and demonstrated that HDMC induced apoptosis in various nonsmall cell lung cancer cells. Further study showed that HDMC elevated cellular reactive oxygen species (ROS) levels, thus inducing expressions of ATF4 and C/EBP homologous protein (CHOP). Then, death receptor 5 (DR5) was upregulated through ATF4-CHOP axis and eventually resulted in apoptosis. We also found that downregulation of c-FLIPL contributed to HDMC-induced apoptosis. In conclusion, HDMC induces apoptosis in human nonsmall cell lung cancer cells via activation of DR5 signaling pathway, and ROS-mediated ATF4-CHOP axis is involved in the process. Our results further supported the potential for HDMC to be developed as a new antitumor agent for cancer therapy or chemoprevention. © 2013 IUBMB Life, 2013.
International Union of Biochemistry and Molecular Biology Life 04/2013; · 3.51 Impact Factor
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ABSTRACT: LKB1 is a Ser/Thr kinase, and its activity is regulated by the pseudokinase, STE20-related adaptor α (STRADα). The STRADα-LKB1 pathway plays critical roles in epithelial cell polarity, neuronal polarity, and cancer metastasis. Though much attention is given to the STRADα-LKB1 pathway, the function of STRADα itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in Caenorhabditis elegans suggest that STRADα has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRADα regulates cancer cell polarity and motility when wild-type LKB1 is absent. These results show that STRADα protein is reduced in LKB1-null cell lines (mutation or homozygous deletion) and this partial degradation occurs through the Hsp90-dependent proteasome pathway. The remaining STRADα participates in cell polarity and invasion, such that STRADα depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRADα associates in a complex with PAK1, and STRADα loss disrupts PAK1 activity via Thr(423) PAK1 phosphorylation. When STRADα is depleted, PAK1-induced invasion could not occur, suggesting that STRADα is necessary for PAK1 to drive motility. Furthermore, STRADα overexpression caused increased activity of the PAK1-activating protein, rac1, and a constitutively active rac1 mutant (Q61L) rescued pPAK(Thr423) and STRADα invasion defects. Taken together, these results show that a STRADα-rac1-PAK1 pathway regulates cell polarity and invasion in LKB1-null cells. It also suggests that while the function of LKB1 and STRADα undoubtedly overlap, they may also have mutually exclusive roles.
Journal of Biological Chemistry 04/2012; 287(22):18758-68. · 4.77 Impact Factor
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Zhongguo fei ai za zhi = Chinese journal of lung cancer 08/2011; 14(8):685-8.
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ABSTRACT: Sirtuins (a class III histone deacetylase) have emerged as novel targets for cancer therapy. Salermide, a reverse amide compound that inhibits Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2), has been shown to induce apoptosis in human cancer cells. The mechanism underlying cellular apoptotic signalling by salermide remains unclear. In this study, we show that salermide up-regulates the expression of death receptor 5 (DR5) in human non-small cell lung cancer (NSCLC) cells. Blocking DR5 expression by gene silencing technology results in a decrease in activated forms of several pro-apoptotic proteins (caspase-8, caspase-9, caspase-3, PARP). Increasing DR5 protein expression correlates with salermide-induced apoptosis in human NSCLC cells. We discovered that IRE-1α, Bip, activating transcription factor 3 (ATF4), activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP) are induced by salermide, which suggests that DR5-dependent apoptosis is induced by endoplasmic reticulum stress. Moreover, knockdown of Sirt1 and Sirt2 expression resulted in up-regulation of ATF4, CHOP and DR5. Transfected NSCLC cells with ATF4, ATF3 or CHOP siRNA results in a decline in pro-apoptotic proteins (such as caspase-8, caspase-9, caspase-3 and PARP) despite salermide treatment. We demonstrate that salermide induces expression of ATF4, and ATF4 up-regulates ATF3 and subsequently modulates CHOP. This suggests that DR5 is modulated by the ATF4-ATF3-CHOP axis in NSCLC after Sirt1/2 inhibition or salermide treatment. This study highlights the importance of DR5 up-regulation in apoptosis induced by Sirt1/2 inhibition and elucidates the underlying mechanism in human NSCLC cells.
Journal of Cellular and Molecular Medicine 07/2011; 16(7):1618-28. · 4.13 Impact Factor
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ABSTRACT: Pemetrexed is a clinically available anti-folate therapeutic agent used in combination with cisplatin for the management of patients with malignant pleural mesothelioma and advanced non-small cell lung cancer. Pemetrexed inhibits three enzymes in purine and pyrimidine synthesis necessary for precursor DNA nucleotides which in turn disrupts growth and survival of normal and cancer cells. The mechanism by which pemetrexed induces apoptosis remains largely uncharacterised. In the current study, we examined the downstream effect of pemetrexed in inducing apoptosis in lung cancer cells. We showed that pemetrexed induced apoptosis via up-regulation of Death Receptor 5 (DR5), an important death receptor for tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). In addition, we discovered a synergistic effect of combination pemetrexed and recombinant TRAIL in inducing apoptosis. Modulating DR5 induction by small interfering RNA abrogated the ability of pemetrexed to induce apoptosis. In addition, silencing of C/EBP homologous protein (CHOP) expression reduced DR5 expression, demonstrating that the transcriptional factor CHOP has a pivotal role on DR5 up-regulation following pemetrexed treatment. In addition, enforced expression of cellular FLICE-inhibitory protein (c-FLIP), a known inhibitor of caspase 8, protected neoplastic cells from apoptosis despite pemetrexed and/or TRAIL therapy. Thus, our findings demonstrate the efficacy and mechanistic underpinnings of pemetrexed-induced apoptosis, and they suggest pemetrexed may have clinical utility when used in combination with TRAIL for the management of patients with lung cancer.
European journal of cancer (Oxford, England: 1990) 07/2011; 47(16):2471-8. · 4.12 Impact Factor
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Zhongguo fei ai za zhi = Chinese journal of lung cancer 01/2011; 14(1):72-4.
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Zhongguo fei ai za zhi = Chinese journal of lung cancer 11/2010; 13(11):1079-81.
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Zhongguo fei ai za zhi = Chinese journal of lung cancer 09/2010; 13(9):917-9.
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Zhongguo fei ai za zhi = Chinese journal of lung cancer 05/2010; 13(5):391-2.
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ABSTRACT: Fourty years ago, Tokuhata and Lilienfeld provided the first epidemiologic evidence of familial aggregation of lung cancer. Familial aggregation and increased familial risk for lung cancer have been reported in several studies, subsequently. But the results are not consistent with each other. The aim of this study is to further explore the relationship between family history of lung cancer and lung cancer risk.
By searching PubMed, CENTRAL, CBM, CNKI and VIP, we collected both domestic and overseas published documents before November, 2009 on family history of lung cancer and lung cancer risk. RevMan version 4.2 was used to perform meta-analysis on the case-control study results, the combined odds ratio (OR) and the 95% confidence interval (CI) were calculated as well.
Twenty-eight publications were included into the combined analysis, which indicated that the lung cancer risk of the probands' first-degree relatives was 1.88 times higher than that of their controls' (P < 0.001). In the sub-study, compared with the controls' father mother and siblings, the OR of the probands' father mother and siblings was 1.62 (P < 0.001), 1.96 (P < 0.001) and 1.92 (P < 0.001), respectively. For smoking status, lung cancer risk in first-degree relatives of smoking probands was 1.73 (P < 0.001) times higher than that of their corresponding controls'. And for non-smoking subjects the lung cancer risk was 1.42 (P = 0.02) times higher in proboands' first-degree relatives. For gender categories, lung cancer risk in first-degree relatives of female probands was 1.89 (P < 0.001) times higher than that of their corresponding controls'. And for male subjects, the lung cancer risk was 1.99 (P < 0.001) times higher in proboands' first-degree relatives.
Lung cancer risk was increased in probands' first-degree relatives, and obvious familial aggregation of lung cancer was observed in this study.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 03/2010; 13(3):224-9.
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Diansheng Zhong,
Li Xiong,
Tongrui Liu,
Xiuju Liu,
Xiangguo Liu,
Jing Chen,
Shi-Yong Sun,
Fadlo R Khuri,
Yaping Zong,
Qinghua Zhou,
Wei Zhou
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ABSTRACT: Recent molecular studies indicate that aerobic glycolysis plays an important role in tumorigenesis and is a valid target for cancer therapy. Although 2-deoxyglucose (2-DG) is well characterized as a glycolytic inhibitor, we recently discovered that it activates a prosurvival oncoprotein, AKT, through PI3K. In this study, we discovered that 2-DG treatments disrupted the binding between insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP3) so that the free form of IGF-1 could be released from the IGF-1.IGFBP3 complex to activate IGF-1 receptor (IGF1R) signaling. Because IGF1R signaling is involved, PI3K/AKT constitutes only one of the prosurvival pathways that are activated by 2-DG treatment; we validated that MEK-ERK signaling was also induced in an IGF1R-dependent manner in some cancer cell lines. Furthermore, our phospho-specific antibody microarray analysis indicated that 2-DG up-regulated the phosphorylation of 64 sites within various signaling pathways in H460 cells. Chemical inhibition of IGF1R reduced 57 of these up-regulations. These data suggest that 2-DG-induced activation of many survival pathways can be jointly attenuated through IGF1R inhibition. Our in vitro analysis demonstrated that treatment with a combination of subtoxic doses of 2-DG and the IGF1R inhibitor II reduced cancer cell proliferation 90% and promoted significant apoptosis.
Journal of Biological Chemistry 08/2009; 284(35):23225-33. · 4.77 Impact Factor
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Lizheng Guo, Diansheng Zhong,
Stephen Lau,
Xiuju Liu,
Xue-Yuan Dong,
Xiaodong Sun,
Vincent W Yang,
Paula M Vertino,
Carlos S Moreno,
Vijay Varma,
Jin-Tang Dong,
Wei Zhou
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ABSTRACT: The presence of somatic beta-catenin mutations in some prostate cancers implies that aberrant WNT signaling is involved in the cancer development. Although beta-catenin stability is regulated by a multicomponent destruction complex, mutational alterations of beta-catenin or other components of the destruction complexes are rare in prostate tumors. Therefore, beta-catenin may be regulated by another protein in the prostate. In fact, recent linkage and somatic deletion analyses in prostate cancers reveal a 1.4-Mb candidate tumor suppressor locus on 8p23.1, which includes the Sox7 gene. Here we show that Sox7 protein expression was indeed down-regulated in 47% (15 of 32) of prostate adenocarcinomas. In addition, Sox7 mRNA was down-regulated in 60% of snap-frozen tumors. This down-regulation was found to be due to tumor-specific promoter hypermethylation, which was present in 48% (10 of 21) of primary prostate tumors and 44% (11 of 25) of prostate cancer cell lines/xenografts. We discovered that Sox7 protein physically interacts with beta-catenin and suppresses beta-catenin-mediated transcription by depleting active beta-catenin. Furthermore, in HCT116 colorectal cancer cell lines with Sox7 inactivation, ectopic Sox7 expression suppressed cell proliferation and inhibited transcription that was activated by an endogenous mutant beta-catenin. Although nearly all colorectal cancers contain mutations in beta-catenin or adenomatous polyposis coli/axin, epigenetic silencing of Sox7 was still observed. These data suggest that Sox7 is a tumor suppressor that functions as an independent checkpoint for beta-catenin transcriptional activity. Inactivation of Sox7 could promote the development of a majority of colorectal tumors and approximately half of prostate tumors.
Molecular Cancer Research 10/2008; 6(9):1421-30. · 4.29 Impact Factor
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ABSTRACT: LKB1 plays the role of tumor suppressor, opposite to Akt, by negatively regulating mammalian target of rapamycin through the activation of AMP-activated protein kinase and TSC signaling. We have discovered a novel, potentially oncogenic role for LKB1 as a supporter of Akt-mediated phosphorylation of proapoptotic proteins. We found that Akt activation led to increased phosphorylation of FoxO3a at Thr(32) in LKB1 wild-type cells but not in LKB1-null cells. Depletion of LKB1 in the cells with wild-type LKB1 resulted in attenuation of that phosphorylation of FoxO3a by activated Akt, whereas the restoration of LKB1 function in LKB1-null cells reestablished Akt-mediated FoxO3a phosphorylation. On expanding our analysis to other Akt targets, using isogenic LKB1 knockdown cell line pairs and a phospho-specific antibody microarray, we observed that there was a requirement for LKB1 in the phosphorylation of other Akt downstream targets, including Ask1 (Ser(83)), Bad (Ser(136)), FoxO1 (Ser(319)), FoxO4 (Ser(197)), and glycogen synthase kinase 3beta (GSK3beta; Ser(9)). Because the phosphorylation of these sites by Akt suppresses apoptosis, the requirement of LKB1 suggests that LKB1 may have an antiapoptotic role in tumor cells with constitutively active Akt. Indeed, we found that the suppression of LKB1 expression led to apoptosis in three cell lines in which Akt is constitutively active but not in two cell lines without Akt activation. This observation may explain the lack of LKB1 somatic mutations in brain, breast, and colon cancers, where Akt is frequently activated due to mutations in phosphatidylinositol 3-kinase, PTEN, or Akt itself.
Cancer Research 10/2008; 68(18):7270-7. · 7.86 Impact Factor
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ABSTRACT: Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1alpha protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1alpha gene transcription, EF24 exerted its activity by inhibiting HIF-1alpha posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24.
Cell cycle (Georgetown, Tex.) 09/2008; 7(15):2409-17. · 5.36 Impact Factor
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ABSTRACT: The compound 2-deoxyglucose (2-DG) enhances chemotherapy/radiotherapy in cell lines and animal models, prompting two phase I clinical trials with this cancer therapeutic. Although its mechanism of action has not been fully elucidated, it is hypothesized that the molecular basis of 2-DG activity is related to glycolysis inhibition. Here, we report that 2-DG induced Akt phosphorylation at Thr(308) and Ser(473) as early as 15 min post-treatment. These phosphorylation events required phosphatidylinositol-3-kinase activity but were not related to LKB1/AMP-activated protein kinase signaling, the inhibition of glycolysis or epidermal growth factor receptor signaling. The 2-DG-mediated Akt phosphorylation also led to the phosphorylation of Akt downstream targets, such as Foxo3a, GSK3beta, and Chk1. Because the functional consequence of Akt activation includes chemotherapy/radiotherapy resistance, our data suggested that the combination of phosphatidylinositol-3-kinase/Akt inhibitory agents in 2-DG-based chemotherapy/radiotherapy may result in enhanced therapeutic efficacy.
Molecular Cancer Therapeutics 05/2008; 7(4):809-17. · 5.23 Impact Factor
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ABSTRACT: Germline inactivation of LKB1 is responsible for Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by benign hamartomas of the GI tract and an increased predisposition to certain cancers, including lung. Acquired mutations in LKB1 are rarely observed in most sporadic tumor types except for adenocarcinomas of the lung where up to 50% harbor inactivating mutations. In this study, we focused on LKB1 mutations in lung cancer cell lines originating from large cell carcinomas. We identified a novel 1.5kb interstitial deletion within LKB1 gene in H157 cancer cells. Homozygosity mapping-of-deletion analysis (HOMOD) analysis showed that the deletion is accompanied by LOH of one parental allele, indicating biallelic inactivation of LKB1. This deletion results in an LKB1 transcript lacking exons 2 and 3 and a predicted in-frame deletion of 58 amino acids within the kinase domain of the LKB1 protein. The truncated transcript was expressed at relatively low levels, and the truncated LKB1 protein was virtually undetectable in this cell line. To determine the impact of LKB1 protein truncation on its function, we examined AMPK-alpha, a downstream target of LKB1 kinase activity triggered by low energy stress conditions. Phosphorylation of AMPK-alpha was attenuated in H157 cells treated with 2-deoxyglucose, and could be rescued by expression of an exogenous GFP-LKB1 fusion protein. Therefore, our data suggest that LKB1 function is compromised in H157. Of the four cell lines and six primary tumors of large cell lung carcinoma origin that have been evaluated in this and other studies, LKB1 mutations have been found in three cases. These results suggest that, in addition to adenocarcinomas, acquired loss of function mutations in LKB1 may also be frequently involved in the pathogenesis of large cell lung carcinomas.
Lung Cancer 10/2006; 53(3):285-94. · 3.43 Impact Factor
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ABSTRACT: Inactivation of TGF-beta/SMAD4 signaling was postulated to play an important role in breast cancer development. Even though SMAD4 is located on 18q21, a region frequently lost in breast cancers, point mutations of SMAD4 were rarely observed, implying that biallelic inactivation of SMAD4 was not necessary in the process. In this study, a novel homozygous deletion of SMAD4 was identified in breast cancer cell line SW527 during a screening of 31 breast cancer cell lines. As several breast cancer cell lines were shown to contain SMAD4 homozygous deletion, we sought to develop a reliable method to access such lesions in archived primary tumor specimens. First, a DNA quantification method was developed to measure as few as 5 copies of DNA templates so that the amount of genomic DNA isolated by laser-capture microdissection can be accurately determined. Next, accurate DNA quantitation allowed sufficient DNA templates to be included in the homozygous deletion assay for the robust amplification of SMAD4 genetic markers. Two out of 24 primary infiltrative ductal carcinomas (IDC) with 18q allelic imbalance were determined to contain SMAD4 homozygous deletions, and these samples are also negative for Smad4 protein expression by immunohistochemistry. Our data suggest that biallelic inactivation of SMAD4 through homozygous deletion does occur in a small percentage of IDCs, and support the hypothesis that inactivation of TGF-beta/SMAD4 signaling plays in a role in the development of a subset of IDC.
Cancer biology & therapy 07/2006; 5(6):601-7. · 2.64 Impact Factor
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ABSTRACT: Identification of breast cancer patients at risk for postoperative distant relapse is an important clinical issue. Existing pathological markers can predict disease recurrence only to a certain extent, and there is a need for more accurate predictors.
Using 'counting alleles', a novel experimental method, we determined allelic status of chromosomes 8p and 18q in a case-control study with 65 early stage, node negative, invasive ductal carcinomas (IDCs). The association between allelic imbalance (AI) of both chromosomal markers and distant relapses was examined.
Eighty percent of tumors contained 8pAI and sixty-eight percent of tumors contained 18qAI. However, none of the tumor samples retained both chromosome 8p and 18q alleles. More importantly, tumors with 8pAI but not 18qAI were more likely to have distant relapse compared to tumors with 18qAI but not 8pAI.
Our finding suggests that differential allelic loss of chromosomes 8p and 18q may represent subtypes of early stage IDC with different tumor progression behaviors.
Breast cancer research: BCR 02/2005; 7(6):R1051-7. · 5.24 Impact Factor
