Carcinogenesis (Carcinogenesis)

Publications in this journal

• Article: Downregulation of ASPP2 in choriocarcinoma contributes to increased migratory potential through Src signaling pathway activation.

  Victor C Y Mak, Lee Lee, Michelle K Y Siu, Oscar G W Wong, Xin Lu, Hextan Y S Ngan, Esther S Y Wong, Annie N Y Cheung
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  ABSTRACT: Gestational choriocarcinoma is a malignant tumour derived from placental trophoblast and the most aggressive member of gestational trophoblastic disease (GTD). Apoptotic stimulating protein of p53-2 (ASPP2) is a member of ASPP family that transactivates p53 and thereby functions as a tumour suppressor. In this study, the expression profile of ASPP2 in choriocarcinoma was examined in comparison with normal placentas and hydatidiform moles, the latter being a type of GTD that carries malignant potential. Downregulation of ASPP2 mRNA and protein was demonstrated in choriocarcinoma by quantitative PCR and immunohistochemistry. ASPP2-transfected choriocarcinoma cells (JEG-3 and JAR) showed an increase in apoptosis and a decrease in cell migration as detected by TUNEL and wound healing assays, respectively, illustrating the complex action of ASPP2 on cell functions other than programmed cell death. Activated Src is known to be important in tumour progression. Transfection of ASPP2 but not ASPP1, another tumour suppressive ASPP, was found to be related to subsequent decreased Src-pY416 phosphorylation, suggesting an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-mediated inactivation of Src could be abolished by RNA interference with Csk, a kinase that can inhibit Src activation. Our findings suggested that the ability of ASPP2 to attenuate Src activation was specific to ASPP2 in a Csk dependent manner. Taken together, we demonstrated a loss of tumour suppressive ASPP2 in choriocarcinoma with effects on cell migration as well as apoptosis. We also unveiled a possible mechanistic link between ASPP2 and Csk/Src signaling pathway, implicating the multiple cellular functions of ASPP2.
  Carcinogenesis 05/2013;
• Article: (S)-N'-Nitrosonornicotine, a Constituent of Smokeless Tobacco, is a Powerful Oral Cavity Carcinogen in Rats.

  Silvia Balbo, Sandra James-Yi, Charles S Johnson, M Gerald O'Sullivan, Irina Stepanov, Mingyao Wang, Dipankar Bandyopadhyay, Fekadu Kassie, Steven Carmella, Pramod Upadhyaya, Stephen S Hecht
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  ABSTRACT: Currently, smokeless tobacco products are being proposed as an alternative mode of tobacco use associated with less harm. All of these products contain the tobacco-specific carcinogen N(')-nitrosonornicotine (NNN). The major form of NNN in tobacco products is (S)-NNN, shown in this study to induce a total of 89 benign and malignant oral cavity tumors in a group of 20 male F-344 rats treated chronically with 14 ppm in the drinking water. The opposite enantiomer (R)-NNN was inactive, but synergistically enhanced the carcinogenicity of (S)-NNN. Thus, (S)-NNN is identified for the first time as a strong oral cavity carcinogen in smokeless tobacco products and should be significantly reduced or removed from these products without delay in order to prevent debilitating and deadly oral cavity cancer in people who use them.
  Carcinogenesis 05/2013;
• Article: The Metastasis Suppressor, NDRG1: Mediates its Activity Through Signaling Pathways and Molecular Motors.

  Jing Sun, Daohai Zhang, Dong-Hun Bae, Sumit Sahni, Patric Jansson, Ying Zheng, Qian Zhao, Fei Yue, Minhua Zheng, Zaklina Kovacevic, Des R Richardson
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  ABSTRACT: The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, being a promising new target for cancer treatment. However, the precise molecular effects of NDRG1 remain unclear. Herein, we summarize recent advances in understanding the impact of NDRG1 on cancer metastasis with emphasis on its interactions with the key oncogenic NF-κB, PI3K/pAKT/mTOR and Ras/Raf/MEK/ERK signaling pathways. Recent studies demonstrating the inhibitory effects of NDRG1 on the epithelial-mesenchymal transition (EMT), a key initial step in metastasis, as well as the WNT/β-catenin pathway are also described. Furthermore, NDRG1 was also demonstrated to regulate molecular motors in cancer cells, leading to inhibition of F-actin stress fiber formation and subsequent reduction of cancer cell migration. Collectively, this review summarizes the underlying molecular mechanisms of the anti-metastatic effects of NDRG1 in cancer cells.
  Carcinogenesis 05/2013;
• Article: MiR-146a enhances angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting PDGFRA expression.

  Kai Zhu, Qi Pan, Xin Zhang, Ling-Qun Kong, Jia Fan, Zhi Dai, Lu Wang, Xin-Rong Yang, Jie Hu, Jin-Liang Wan, Yi-Ming Zhao, Zhong-Hua Tao, Zong-Tao Chai, Hai-Ying Zeng, Zhao-You Tang, Hui-Chuan Sun, Jian Zhou
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  ABSTRACT: Endothelial cells are critical for angiogenesis, and microRNA play important roles in this process. We investigated the regulatory role of microRNAs in endothelial cells of hepatocellular carcinoma (HCC) by examining the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) in the absence or presence of human HCC cells, and identified miR-146a as the most highly up-regulated microRNA. Furthermore, we revealed that miR-146a promoted the expression of platelet-derived growth factor receptor α (PDGFRA) in HUVECs, and this process was mediated by BRCA1. Overexpression of PDGFRA in the ECs of HCC tissues was associated with microvascular invasion, and predicted a poorer prognosis. These results suggest that MiR-146a plays a key role in regulating the angiogenic activity of ECs in HCC through miR-146a-BRCA1-PDGFRA pathway. MiR-146a may emerge as a potential anti-angiogenic target on ECs for HCC therapy.
  Carcinogenesis 05/2013;
• Article: *Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2-epoxide isomers of dibenz[a,h]anthracene.

  Richard L Chang, Alexander W Wood, Mou-Tuan Huang, Jian Guo Xie, Xiao Xing Cui, Kenneth R Reuhl, Derek R Boyd, Yong Lin, Weichung Joe Shih, Suresh K Balani, Harujiko Yagi, Donald M Jerina, Allan H Conney
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  ABSTRACT: Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of S. typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide 2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide 1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity.In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)- 3β,4α-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin whereas (+)-(3S,4S)-3α,4β-dihydroxy-3,4- dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice.
  Carcinogenesis 05/2013;
• Article: PTTG1 Promotes Migration and Invasion of Human Non-small Cell Lung Cancer Cells and is modulated by miR-186.

  Hongli Li, Chonggao Yin, Baogang Zhang, Yonghong Sun, Lihong Shi, Ningbo Liu, Shujuan Liang, Shijun Lu, Yuqing Liu, Jin Zhang, Fengjie Li, Wentong Li, Fei Liu, Lei Sun, Yueliang Qi
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  ABSTRACT: Deeper mechanistic understanding of non-small cell lung cancer (NSCLC), a leading cause of total cancer-related deaths, may facilitate the establishment of more effective therapeutic strategies. In this study, pituitary tumor transforming gene (PTTG1) expression was associated with lymph node and distant metastasis in patients with NSCLC and was correlated with patient survival. Reduction of PTTG1 by siRNA inhibits the migration and invasion of NSCLC cells by mediating MMPs expression. To the best of our knowledge, this study is the first to report that PTTG1 promotes EGF-induced the phosphorylation of LIN-11, Isl1, and MEC-3 protein domain kinase and cofilin, a critical step in cofilin recycling and actin polymerization. Additionally, EGF-induced Akt phosphorylation was suppressed through knockdown of PTTG1. Interestingly, miR-186 can modulate PTTG1 protein expression. As observed from the animal experiment in the present study, knockdown of PTTG1 through siRNA and overexpression of miR-186 inhibited invasive activity of NSCLC cells toward the SCID mice lung. In summary, our in vitro and in vivo results indicate that PTTG1 modulated by miR-186 has an important function in NSCLC invasion/metastasis. This study identified both PTTG1 and miR-186 as potential anti-invasion targets for therapeutic intervention in NSCLC.
  Carcinogenesis 05/2013;
• Article: SB365, Pulsatilla saponin D targets c-Met and exerts antiangiogenic and anti-tumor activities.

  Sang-Won Hong, Kyung Hee Jung, Hee-Seung Lee, Mi Kwon Son, Hong Hua Yan, Nam Sook Kang, Jongkook Lee, Soon-Sun Hong
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  ABSTRACT: SB 365, Pulsatilla saponin D isolated from the root of Pulsatilla koreana has exhibited potential beneficial effects as a chemopreventive agent for critical health conditions including cancer. However, the molecular mechanisms underlying the activity of SB365 remain unknown. Here, we examined anticancer efficacy of SB365 against gastric cancer and its mechanism of action. SB365 effectively inhibited the growth of gastric cancer cells. Its apoptotic effect was accompanied by increased evidence of cleaved caspase-3 and PARP. To elucidate the anticancer mechanism of SB365, we used an array of 42 different receptor tyrosine kinase (RTKs). Of the 42 different phospho-RTKs, SB365 strongly inhibited expression of activated c-Met in gastric cancer cells. Also, the activation of the c-Met signal cascade components, including Akt and mTOR, were inhibited by SB365 in a dose-dependent manner. In angiogenesis studies, SB365 inhibited tube formation in hepatocyte growth factor (HGF)-induced human umbilical vein endothelial cells, and suppressed microvessel sprouting from the rat aortic ring, ex vivo, and blood vessel formation in the Matrigel plug assay in mice. In xenograft animal models, SB365 significantly delayed tumor growth in a dose-dependent manner. In tumor tissue, SB365 suppressed c-Met signaling, proliferation, and angiogenesis, and induced apoptosis. These findings suggest that SB365 docks at an allosteric site on c-Met, and thereby targets c-Met signaling pathway, cell growth/angiogenesis inhibition, and apoptosis induction. Therefore, SB365 may be a novel drug candidate for the treatment of gastric cancer.
  Carcinogenesis 05/2013;
• Article: SGEF enhances EGFR stability through delayed EGFR trafficking from early to late endosomes.

  Hongtao Wang, Shan-Hu Li, Hailiang Li, Changling Li, Kaopeng Guan, Guolan Luo, Lan Yu, Rui-Qin Wu, Xiaoqing Zhang, Jian Wang, Jianguang Zhou
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  ABSTRACT: Previously we demonstrated an elevated SGEF expression in clinical specimens with prostate cancer and implicated the role of SGEF in prostate tumorigenesis. However, the molecular mechanism behind the SGEF regulation of prostate cancer development is not known. In this study, we show that SGEF expression delays epidermal growth factor receptor (EGFR) degradation in prostate cancer cells and is independent from its guanine nucleotide exchange (GEF) function. We further show that the delayed degradation is due to a delay in EGFR trafficking from early to late endosomes and not to a decrease in EGFR ubiquitination. Finally, we show that depletion of SGEF significantly inhibits EGF induced EGFR signaling cascade and cell migration in the prostate cancer cells. We report for the first time a SGEF function for RhoG that excludes GEF and the ability of SGEF to enhance EGFR stability and sig¬naling by delaying its lysosomal sorting and degradation. This could be one mechanism by which SGEF contributes to prostate cancer progression.
  Carcinogenesis 05/2013;
• Article: High Circulating Estrogens and Selective Expression of ERβ in Prostate Tumors: Implications for Racial Disparity of Prostate Cancer.

  Zakaria Y Abd Elmageed, Krzysztof Moroz, Sudesh K Srivastav, Zhide Fang, Byron E Crawford, Krishnarao Moparty, Raju Thomas, Asim B Abdel-Mageed
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  ABSTRACT: Although estrogen receptor beta (ERβ) has been implicated in prostate cancer (PCa) progression, its potential role in health disparity of PCa remains elusive. The objective of this study was to examine serum estrogens and prostate tumor ERβ expression and examine their correlation with clinical and pathological parameters in African American (AA) versus Caucasian American (CA) men. The circulating 17β-Estradiol (E2) was measured by EIA in blood procured from racially stratified normal subjects and PCa patients. Differential expression profile analysis of ERβ was analyzed by quantitative IHC using ethnicity-based tissue microarray encompassing 300 PCa tissue cores. In situ ERβ expression was validated by qRT-PCR in matched microdissected normal prostate epithelium and tumor cells and datasets extracted from independent cohorts. Circulating E2 levels are significantly elevated in PCa patients in comparison to normal age-matched subjects. However, further analysis an increase in blood E2 levels in AA-men, both normal and PCa, than in counterparts of CA decent. Histoscore (HS) analysis reveals intense nuclear immunoreactivity for ERβ in tumor cores of AA than in CA men. Gene expression analysis in microdissected tumors corroborated the biracial differences in ERβ expression. Gene expression analysis from independent cohort datasets revealed correlation between ERβ expression and PCa progression. However, unlike in CA men, adjusted multivariate analysis showed that ERβ expression correlates with age at diagnosis and low PSA recurrence-free survival in AA men. Taken together, our results suggest that 17β-Estradiol-ERβ axis may have potential clinical utility in PCa diagnosis and clinical outcome among AA men.
  Carcinogenesis 05/2013;
• Article: Imputation-based association analyses identify new lung cancer susceptibility variants in CDK6 and SH3RF1 and their interactions with smoking in Chinese populations.

  Qifei Deng, Huan Guo, Juncheng Dai, Lei Yang, Chen Wu, Qing Wang, Zhibin Hu, Ming Yang, Li Liu, Dianke Yu, [......], Jing Feng, Kai Teng, Jianhang Gong, Chongqi Sun, Xiaoyan Hu, Kai Zhang, Jiachun Lu, Dongxin Lin, Hongbing Shen, Tangchun Wu
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  ABSTRACT: Cell cycle regulation, apoptosis, oxidative stress, and inflammation response play critical roles in the development of smoking-induced lung cancer. However, it is still not well known whether their genetic variants are associated with lung cancer susceptibility. Here we performed imputation-based association analyses to investigate the influence of common genetic variants in these pathways and their interactions with smoking on lung cancer susceptibility. We first selected 24 042 unvalidated genetic variants in 798 genes from the imputed dataset of the previous lung cancer genome-wide association study (GWAS) in 2331 cases and 3077 controls, and then conducted additional two-stage validations in 4133 cases and 4522 controls. We found a genome-wide significant (P < 5.0×10(-8)) association for rs2282987 in CDK6 at 7q21.2 [odds ratio (OR) = 1.18, combined Padd = 2.27×10(-9)] and a consistent association for rs2706748 in SH3RF1 at 4q32.3 (OR = 1.17, combined Padd = 5.10×10(-6)). Interaction analyses showed that rs2282987 and rs2706748 interacted with both smoking status (Pinteraction were 1.04×10(-2) and 3.03×10(-2), respectively) and smoking dose (Pinteraction were 1.21×10(-2) and 5.21×10(-2), respectively) to contribute to lung cancer susceptibility in subjects aged 50 to 60 years. These results further underscore the contribution of genetic variants involved in pathways of cell cycle regulation and apoptosis to lung cancer susceptibility, and highlight gene-environment interactions in lung cancer etiology, especially in subjects aged 50 to 60 years.
  Carcinogenesis 05/2013;
• Article: Deficiency of caveolin-1 in Apcmin/+ mice promotes colorectal tumorigenesis.

  Teresa Friedrich, Birgit Richter, Timo Gaiser, Christel Weiss, Klaus-Peter Janssen, Henrik Einwäechter, Roland M Schmid, Matthias P A Ebert, Elke Burgermeister
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  ABSTRACT: Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor (PPARγ), inhibits oncogenic signaling through Ras and wingless (WNT). However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1(-/-)) mice. Apc(min/+) Cav1(-/-) mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1(+/-) and Apc(min/+) Cav1(+/+) littermates. Intratumoral gene signatures related to Ras and WNT signaling were elevated, nuclear localization of PPARγ protein and expression of PPARγ-target genes were reduced independently of Cav1. The PPARγ-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and up-regulated expression of the Ras-inhibitory protein docking protein-1 (Dok1). Thus, codeficiency of Cav1 and adenomatous polyposis coli (APC) facilitated formation of CRC, and activation of PPARγ may offer novel strategies for treatment of CRC.
  Carcinogenesis 05/2013;
• Article: Survivin promotion of melanoma metastasis requires upregulation of α5 integrin.

  Jodi A McKenzie, Tong Liu, Jae Y Jung, Benjamin B Jones, Atakan Ekiz, Alana L Welm, Douglas Grossman
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  ABSTRACT: Survivin is an apoptotic and mitotic regulator that is overexpressed in melanoma, and a poor prognostic marker in patients with metastatic disease. We recently showed that Survivin enhances melanoma cell motility through Akt-dependent upregulation of α5 integrin. However, the functional role of Survivin in melanoma metastasis is not clearly understood. We found that overexpression of Survivin in LOX and YUSAC2 human melanoma cells increased colony formation in soft agar, and this effect was abrogated by knockdown of α5 integrin by RNA interference. We employed melanoma cell xenografts to determine the in vivo effect of Survivin overexpression on melanoma metastasis. While Survivin overexpression did not affect primary tumor growth of YUSAC2 or LOX subcutaneous tumors, or indices of proliferation or apoptosis; it significantly increased expression of α5 integrin in the primary tumors and formation of metastatic colonies in the lungs. Additionally, Survivin overexpression resulted in enhanced lung colony formation following intravenous injection of tumor cells in vivo and increased adherence to fibronectin-coated plastic in vitro. Importantly, in vivo inhibition of α5 integrin via intraperitoneal injection of an α5β1 integrin-blocking antibody significantly slowed tumor growth and reduced Survivin-enhanced pulmonary metastasis. Knockdown of α5 integrin in cells prior to intravenous injection also blocked Survivin-enhanced lung colony formation. These findings support a direct role for Survivin in melanoma metastasis which requires α5 integrin, and suggest that inhibitors of α5 integrin may be useful in combating this process.
  Carcinogenesis 05/2013;
• Article: Caffeic Acid Phenethyl Ester (CAPE) Suppresses Melanoma Tumor Growth by Inhibiting PI3K/AKT/XIAP Pathway.

  Kartick C Pramanik, Shashi K Kudugunti, Neel M Fofaria, Majid Moridani, Sanjay K Srivastava
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  ABSTRACT: Our previous studies demonstrated that caffeic acid phenethyl ester (CAPE) suppress the growth of melanoma cells and induce ROS generation, however, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE treated mice showed reduced phosphorylation of PI3K, AKT, mTOR and protein level of XIAP and enhanced the cleavage of caspase-3 and PARP. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of PI3K at Tyr-458, PDK1 at Ser-241, mTOR at Ser-2448 and AKT at Ser-473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. The expression of XIAP, survivin and BCl2 were down-regulated by CAPE in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and PARP. CAPE treatment inhibited AKT kinase activity and increased the nuclear translocation of XIAP. NAC treatment blocked CAPE mediated AKT/XIAP inhibition and protected the cells from apoptosis. CAPE treatment decreased the interaction of AKT with XIAP in an immunoprecipitation study. Our results also revealed that AKT over-expression attenuated the decrease in XIAP and significantly blocked CAPE-mediated apoptosis. Similarly, XIAP over-expression decreased CAPE-induced apoptosis. Taken together, our results suggest that CAPE suppresses PI3K/AKT/XIAP pathway leading to apoptosis in melanoma tumor cells in vitro and in vivo.
  Carcinogenesis 05/2013;
• Article: Polyunsaturated Fatty Acids Affect the Localization and Signaling of PIP3/AKT in Prostate Cancer Cells.

  Zhennan Gu, Jiansheng Wu, Shihua Wang, Janel Suburu, Haiqin Chen, Michael J Thomas, Lihong Shi, Iris J Edwards, Isabelle M Berquin, Yong Q Chen
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  ABSTRACT: AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate groups at positions 3, 4 and 3,4,5 on the inositol ring. In spite of extensive research on AKT, one aspect has been largely overlooked, namely the role of the fatty acid chains on PIPs. PIPs are phospholipids composed of a glycerol backbone with fatty acids at the sn-1 and sn-2 position and inositol at the sn-3 position. Here we show that polyunsaturated fatty acids (PUFA) modify phospholipid content. Docosahexaenoic acid (DHA), an ω3 PUFA, can replace the fatty acid at the sn-2 position of the glycerol backbone, thereby changing the species of phospholipids. DHA also inhibits AKT(T308) but not AKT(S473) phosphorylation, alters PI(3,4,5)P3 (PIP3) and phospho-AKT(S473) protein localization, decreases pPDPK1(S241)-AKT and AKT-BAD interaction, and suppresses prostate tumor growth. Our study highlights a potential novel mechanism of cancer inhibition by ω3 PUFA through alteration of PIP3 and AKT localization and affecting the AKT signaling pathway.
  Carcinogenesis 04/2013;
• Article: Depletion of 4E-BP1 and regulation of autophagy lead to YXM110-induced anti-cancer effects.

  Chin-Yu Lai, Shiow-Lin Pan, Xiao-Ming Yang, Li-Hsun Chang, Ya-Ling Chang, Pan-Chyr Yang, Kuo-Hsiung Lee, Che-Ming Teng
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  ABSTRACT: Natural products have always been a profuse database for developing new chemotherapeutics. YXM110 is a newly synthesized phenanthroquinolizidines that exhibits excellent anti-cancer activity in numerous cancer cells. Here, we examined the anti-cancer mechanisms of YXM110 both in vitro and in vivo. Protein level of 4E-binding protein 1 (4E-BP1), which is crucial in cap-independent translation, was decreased significantly after YXM110 treatment via c-Jun N-terminal kinases (JNK)-mediated proteasomal degradation. Moreover, the effects of YXM110 were associated with several characteristics of autophagy, including accumulation of autophagic vacuoles, elevation of Atg12-Atg5 and LC3-II, and levels of GFP-LC3 puncta. The results suggested that depletion of Mcl-1 contributes to YXM110-triggered autophagy, whereas downregulation of lysosomal-related genes could cause autophagy impairment. Furthermore, YXM110-induced cell death were prevented by autophagy inhibitor 3-methyladenine (3-MA) and Atg5 silencing, indicating that YXM110-mediated autophagy impairment lead to cancer cell death. These data reveal key mechanisms that support the further development of YXM110 as a promising anti-cancer agent.
  Carcinogenesis 04/2013;
• Article: p53 Dysfunction Precedes the Activation of Nuclear Factor-κB During Disease Progression in Mice Expressing Tax, a Human T-cell Leukemia Virus Type 1 Oncoprotein.

  Takeo Ohsugi, Takaomi Ishida, Tatsuya Shimasaki, Seiji Okada, Kazuo Umezawa
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  ABSTRACT: Transgenic (Tg) mice expressing Tax, a human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, develop mature T-cell leukemia/lymphoma. The leukemic cells in Tg mice expressing Tax show p53 dysfunction and nuclear factor-κB (NF-κB) activation, similar to that seen in adult T-cell leukemia/lymphoma (ATLL) cells from patients infected with HTLV-1. However, it is unclear when these effects occur in HTLV-1 carriers during the development of ATLL. Here, we examined p53 function and NF-κB activity before the onset of leukemia in Tax-expressing Tg (Tax-Tg) mice between 4 and 25 months of age. At 4-10 months of age, 71% of mice showed p53 inactivation, without evidence for NF-κB activation, even though tax expression was consistent from 4 to 25 months of age. The decline in p53 function resulted from decreased p53 accumulation after DNA damage. From 11 months of age onwards, 75% of mice showed p53 dysfunction and 37.5% showed constitutive NF-κB activation with the components of p50 and RelB. An NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced NF-κB activity (i.e., p50/RelB), but did not restore p53 function. In vivo experiments, treatment with DHMEQ until 24 months of age prevented the onset of T-cell leukemia in Tax-Tg mice. These results suggest that the Tax-induced decline in p53 function, which is independent of NF-κB activation in the early stage, might be the first stage in the onset of ATLL. NF-κB activity is involved in the later stages of ATLL onset.
  Carcinogenesis 04/2013;
• 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;
• Article: Polar biophenolics in sweet potato greens extract synergize to inhibit prostate cancer cell proliferation and in vivo tumor growth.

  Sushma R Gundala, Chunhua Yang, N Lakshminarayana, Ghazia Asif, Meenakshi V Gupta, Shahab Shamsi, Ritu Aneja
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  ABSTRACT: Polyphenolic phytochemicals present in fruits and vegetables indisputably confer anticancer benefits upon regular consumption. Recently, we demonstrated the growth-inhibitory and apoptosis-inducing properties of polyphenol-rich sweet potato greens extract (SPGE) in cell culture and in vivo prostate cancer xenograft models. However, the bioactive constituents remain elusive. Here, we report a bioactivity-guided fractionation of SPGE based upon differential solvent polarity using chromatographic techniques that led to the identification of a remarkably active polyphenol-enriched fraction, F5, which was ~100-fold more potent than the parent extract as shown by IC50 measurements in human prostate cancer cells. HPLC-UV and mass-spectrometric analyses of the seven SPGE fractions suggested varying abundance of the major phenols, quinic acid (QA), caffeic acid (CA) its ester, chlorogenic (ChA) acid, and isochlorogenic acids, 4,5-di-CQA, 3,5-di-CQA and 3,4-di-CQA, with a distinct composition of the most-active fraction, F5. Sub-fractionation of F5 resulted in loss of bioactivity, suggesting synergistic interactions among the constituent phytochemicals. Quantitative analyses revealed a ~2.6 and ~3.6 fold enrichment of QA and ChA respectively, in F5 and a definitive ratiometric relationship between the isochlorogenic acids. Daily oral administration of 400 mg/kg bw of F5 inhibited growth and progression of prostate tumor xenografts by ~75% in nude mice, as evidenced by tumor volume measurements and non-invasive real-time bioluminescence imaging. These data generate compelling grounds to further examine the chemopreventive efficacy of the most-active fraction of sweet potato greens extract, and suggests its potential usefulness as a dietary supplement for prostate cancer management.
  Carcinogenesis 04/2013;
• Article: Aneuploidy, Oncogene Amplification, and Epithelial to Mesenchymal Transition Define Spontaneous Transformation of Murine Epithelial Cells.

  Hesed M Padilla-Nash, Nicole E McNeil, Ming Yi, Quang-Tri Nguyen, Yue Hu, Danny Wangsa, David L Mack, Amanda B Hummon, Chanelle Case, Eric Cardin, Robert Stephens, Michael J Difilippantonio, Thomas Ried
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  ABSTRACT: Human epithelial cancers are defined by a recurrent distribution of specific chromosomal aneuploidies, a trait less typical for murine cancer models induced by an oncogenic stimulus. After prolonged culture, mouse epithelial cells spontaneously immortalize, transform, and become tumorigenic. We assessed genome and transcriptome alterations in cultures derived from bladder and kidney utilizing SKY, array CGH, FISH, and gene expression profiling. The results show widespread aneuploidy, yet a recurrent and tissue specific distribution of genomic imbalances, just as in human cancers. Losses of chromosome 4 and gains of chromosome 15 are common and occur early during the transformation process. Global gene expression profiling revealed early and significant transcriptional deregulation. Chromosomal aneuploidy resulted in expression changes of resident genes, and consequently in a massive deregulation of the cellular transcriptome. Pathway interrogation of expression changes during the sequential steps of transformation revealed enrichment of genes associated with DNA repair, centrosome regulation, stem cell characteristics, and aneuploidy. Genes that modulate the epithelial to mesenchymal transition and genes that define the chromosomal instability phenotype played a dominant role, and were changed in a directionality consistent with loss of cell adhesion, invasiveness and proliferation. Comparison with gene expression changes during human bladder and kidney tumorigenesis revealed remarkable overlap with changes observed in the spontaneously transformed murine cultures. Therefore, our novel mouse models faithfully recapitulate the sequence of genomic and transcriptomic events that define human tumorigenesis, hence validating them for both basic and preclinical research.
  Carcinogenesis 04/2013;
• Article: Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.

  Mi Jin Yoon, You Jung Kang, In Young Kim, Eun Hee Kim, Ju Ahn Lee, Jun Hee Lim, Taeg Kyu Kwon, Kyeong Sook Choi
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  ABSTRACT: Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is preferentially cytotoxic to cancer cells over normal cells. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL. Monensin (a polyether ionophore antibiotic that is widely used in veterinary medicine) and salinomycin (a compound that is structurally related to monensin and shows cancer stem cell-inhibiting activity) are currently recognized as anticancer drug candidates. In the present study, we show that monensin effectively sensitizes various glioma cells, but not normal astrocytes, to TRAIL-mediated apoptosis; this occurs at least partly via monensin-induced endoplasmic reticulum (ER) stress, CHOP-mediated DR5 upregulation, and proteasome-mediated downregulation of c-FLIP. Interestingly, other polyether antibiotics, such as salinomycin, nigericin, narasin, and lasalocid A, also stimulated TRAIL-mediated apoptosis in glioma cells via ER stress, CHOP-mediated DR5 upregulation and c-FLIP downregulation. Taken together, these results suggest that combined treatment of glioma cells with TRAIL and polyether ionophore antibiotics may offer an effective therapeutic strategy.
  Carcinogenesis 04/2013;