Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma

Longo, Luigia; Platini, Francesca; Scardino, Anna; Alabiso, Oscar; Vasapollo, Giuseppe; Tessitore, Luciana

doi:10.1158/1535-7163.mct-08-0361

Cited by 113 publications

(69 citation statements)

References 46 publications

(60 reference statements)

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“…Our results show that 3-MA down-regulates the expression of Beclin-1 and LC3-I and inhibits the conversion of LC3-I into LC3-II, as well as decreasing the formation of acid vesicles in the cytoplasm of SHG-44 glioma cells. Moreover, 3-MA enhances MG-132-induced cell death and the number of cells in G 2 /M phase, indicating that autophagy has a protective effect on SHG-44 glioma cells, which is consistent with previous studies reporting that inhibition of autophagy enhances or accelerates cell death in malignant tumors [35,36] or reverses tumor cells' resistance to apoptosis [37] .…”

Section: Discussionsupporting

confidence: 92%

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Zhang

Wang

et al. 2009

Acta Pharmacol Sin

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Aim:The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. Methods: The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. Results: MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G 2 /M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G 2 /M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Conclusion: Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.

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Section: Discussionsupporting

confidence: 92%

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Zhang

Wang

et al. 2009

Acta Pharmacol Sin

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“…[27][28][29][30] Hepatitis B virus and hepatitis C virus infections, liver cirrhosis and other inflammation diseases have been examined as potential risk factors for ICC, 31,32 and also potential factors for induction of autophagy. During growth of ICC, tumor cells periodically outstrip in the vasculature, resulting in narrowing blood vessels that causes nutrient starvation and low oxygen.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

Hou

Dong

Tan

et al. 2011

Laboratory Investigation

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Intrahepatic cholangiocellular carcinomas (ICCs) are usually fatal neoplasms originating from bile duct epithelia. However, many cholangiocarcinoma cells are shown to be resistant to chemotherapeutic drugs, which induce cell apoptosis. The role of autophagy and the therapeutic value of autophagy-associated genes are largely unknown in ICC. Here, we showed that autophagy was activated in nutrient starvation and xenograft cholangiocarcinoma cells. Furthermore, expression of autophagic genes and their autophagic activity were higher in clinical ICC specimens than that in normal cholangiocytes separated by laser capture microdissection. Inhibition of autophagy by autophagy inhibitors or siRNA, cholangiocarcinoma cells showed detention of proliferation and increase of apoptosis during nutrient starvation. In addition, autophagy inhibitor treatment or knockdown of beclin 1 suppressed tumor growth and sensitized ICC cells to chemotherapeutic agent-induced cell death. In conclusion, our data showed that autophagy is activated in ICC, and inactivation of autophagy may lead to cell apoptosis and enhance chemotherapy sensitivity. Intrahepatic cholangiocellular carcinoma (ICC) is a malignant neoplasm originating from epithelium of the biliary tree with high mortality. 1 ICC accounts for 5-30% of all primary liver malignancies, and its incidence has been increasing over the last several decades. 2 The mortality from intrahepatic cholangiocarcinoma is very high, with the 5-year survival rates being o15-20% in most series. 3,4 However, the exact molecular mechanisms of biliary epithelium malignant transformation are not well understood. Despite improved diagnostic and operative techniques, the prognosis of ICC remains poor. 5 Indeed, ICC is a type of cancer highly resistant to conventional antineoplastic medicines, 4 which is partially attributed to the property of insensitivity to cell death induced by cytotoxic agents. It is well known that the avoidance of apoptosis is one of the hallmarks of cancer cells, 6 and that failure to induce apoptosis by anticancer treatments contributes to chemotherapeutic failure and tumor progression. Although autophagy, an alternative caspase-independent cell death program, 7 is thought to be used for cancer treatment, its underlying molecular mechanism is still controversial in antineoplastic therapy and also in tumor progression.Autophagy is a conserved catabolic process by which cells themselves digest their organelles. 8 Autophagy has emerged as a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles, and buffering metabolic stress induced under starvation conditions by recycling intracellular constituents. 9 Autophagosomes engulfing organelles then fuse with lysosomes and mature into autolysosomes. Autophagic processes have been well characterized in yeast, and 430 autophagy-related genes that encode the proteins executing autophagy have been identified in the field of yeast genetics. 6,7 The amino acids and fatty acids generated by autophagic degr...

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“…In contrast, autophagy had no effect neither on the etoposide-induced apoptosis under hypoxia, nor on the protection conferred by hypoxia. The inhibition of the expression of Atg5 gene with siRNA has already been reported to promote resistance to chemotherapy [51,52]. However, it has been reported that Atg5 might be cleaved by calpains and truncated Atg5 could stimulate apoptosis by direct interaction with Bcl-XL in the mitochondrial outer membrane [53].…”

Section: Discussionmentioning

confidence: 99%

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

Cosse

Rommelaere

Ninane

et al. 2010

Biochemical Pharmacology

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Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis.In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO 2 but participates in the protective effect of hypoxia against etoposide-induced apoptosis.Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.

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Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma

Cited by 113 publications

References 46 publications

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

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