Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats

Sun, Kai; Guo, X-l; Zhao, Q-d; Yy, Jing; Kou, X-r; Xie, X-q; Zhou, Yiming; Cai, Ning; Gao, Lu; Zhao, Xiaoping; Ss, Zhang; Song, J-r; Li, D; Deng, W-j; Li, Riqing; Mc, Wu; Wei, Lixin

doi:10.1038/cddis.2013.35

Cited by 73 publications

(60 citation statements)

References 38 publications

(44 reference statements)

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“…It does not appear likely that these effects were due to other nonspecific activities of Atg5, as mice with liver-specific KO of Atg7 was also found to develop benign liver tumors in another study, 9,10 and the treatment of rats with chloroquine, which inhibits autophagy, 24 enhanced the development of liver tumors induced by DEN in the early dysplastic stage and suppressed tumor progression in the later stage. 25 Our finding that the ablation of autophagy induced the expression of multiple tumor suppressors in the liver tumors of L-Atg5-KO mice is interesting (Figure 5b). As we found that the loss of autophagy could activate ATM and Chk2 and suppress the expression of MDM2 (Figures 6a and b), the induction of p53 was likely mediated by the DNA-damage response.…”

Section: Discussionmentioning

confidence: 77%

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

et al. 2014

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The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC. Autophagy (i.e., macroautophagy) is important for cells to remove protein aggregates and damaged organelles. Its dysfunction can cause a variety of diseases including cancers. 1,2 However, its role in carcinogenesis is apparently complex, as it has been shown in different reports to positively or negatively regulate carcinogenesis. 3,4 Autophagy apparently can function as a tumor suppressor, as the gene encoding Beclin-1, a component of the phosphatidylinositol-3-kinase class III (PI3KC3) complex that is essential for the initiation of autophagy, is often monoallelically deleted or mutated in breast, ovarian and prostate cancers. 5 Frameshift mutations in Atg2B, Atg5, Atg9B and Atg12 autophagy genes are also often found in gastric and colorectal cancers with microsatellite instability. 6 The tumor suppressor role of autophagy is further supported by the studies using mouse models. It has been shown that the monoallelic deletion of the Beclin-1 gene in mice induced tumor lesions in various tissues, 7 Atg4C-knockout (KO) mice had increased susceptibility to carcinogens for the development of fibrosarcomas 8 and the systemic mosaic KO of Atg5 and the liver-specific KO of Atg7 in mice led to the development of benign liver adenomas. 9,10 Autophagy has also been shown to promote tumor growth. It has been shown that autophagy can enhance the survival of tumor cells in the hypoxic regions of solid tumors. 11 It has also been shown that in cells expressing oncogenic Ras, autophagy is required to promote tumorigenesis by maintaining oxidative metabolism or facilitating glycolysis. 12,13 Moreover, it has also been demonstrate...

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Section: Discussionmentioning

confidence: 77%

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

et al. 2014

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“…Autophagy inhibitor prevented ATO-mediated cell death Autophagy can either inhibited or accelerate tumor cell growth in different cellular contexts [25,26]. Since manipulation of autophagy might be a useful alternative approach for anticancer therapy, we were eager to explore whether the ATO-triggered autophagy in chondrosarcoma cells benefited cell survival or cell death.…”

Section: Ato Suppressed Growth Of Human Chondrosarcoma Cells and Inhimentioning

confidence: 99%

Arsenic trioxide inhibits growth of human chondrosarcoma cells through G2/M arrest and apoptosis as well as autophagy

et al. 2015

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It has been demonstrated that Gli1 is expressed in chondrosarcoma but not in the normal articular cartilage tissues. Downregulating Gli1 by small interfering RNA inhibited chondrosarcoma cells growth. Arsenic trioxide (ATO) has been demonstrated to suppress human cancer cell growth by targeting Gli1. The aim of this study was to investigate the effect of ATO on antineoplastic capability of chondrosarcoma cells. We found that ATO inhibited the growth of chondrosarcoma cells in dose-dependent and time-dependent manners via MTT and colony formation assays. In addition, ATO treatment induced apoptosis and promoted G2/M phase arrest in SW1353 cells as analyzed by flow cytometry assays and Western blotting. Furthermore, we observed that ATO also triggered autophagy by regulating mammalian target of rapamycin (mTOR) phosphorylation. Finally, we found that ATO-mediated cell death could be averted by autophagy inhibitor. Taken together, the current study suggested that ATO had therapeutic efficacy in human chondrosarcoma cells through the promotion of G2/M arrest and induction of both apoptosis as well as autophagy. ATO administration could be a novel therapeutic strategy for treating chondrosarcomas.

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“…This can be explained by the following: (1) there is a relationship of mutual promotion between IS and TRAIL; and (2) IS induced autophagy and ROS at the same time. Autophagy may inhibit ROS accumulation [39, 40]. And TRAIL might inhibit IS-induced autophagy.…”

Section: Discussionmentioning

confidence: 99%

Icariside II overcomes TRAIL resistance of melanoma cells through ROS-mediated downregulation of STAT3/cFLIP signaling

et al. 2016

Oncotarget

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many melanoma cells show weak responses to TRAIL. Here, we investigated whether Icariside II (IS), an active component of Herba Epimedii, could potentiate antitumor effects of TRAIL in melanoma cells. Melanoma cells were treated with IS and/or TRAIL and cell death, apoptosis and signal transduction were analyzed. We showed that IS promoted TRAIL-induced cell death and apoptosis in A375 melanoma cells. Mechanistically, IS reduced the expression levels of cFLIP in a phospho-STAT3 (pSTAT3)-dependent manner. Ectopic expression of STAT3 abolished IS-induced cFLIP down-regulation and the associated potentiation of TRAIL-mediated cell death. Moreover, IS-induced reactive oxygen species (ROS) production preceded down-regulation of pSTAT3/cFLIP via activating AKT, and the consequent sensitization of cells to TRAIL. We also found that IS treatment down-regulated cFLIP via ROS-mediated NF-κB pathway. In addition, IS converted TRAIL-resistant melanoma MeWo and SK-MEL-28 cells into TRAIL-sensitive cells. Taken together, our results indicated that IS potentiated TRAIL-induced apoptosis through ROS-mediated down-regulation of STAT3/cFLIP signaling.

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Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats

Cited by 73 publications

References 38 publications

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis

Arsenic trioxide inhibits growth of human chondrosarcoma cells through G2/M arrest and apoptosis as well as autophagy

Icariside II overcomes TRAIL resistance of melanoma cells through ROS-mediated downregulation of STAT3/cFLIP signaling

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