Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma

Shi, Ying‐Hong; Ding, Zhen–Bin; Zhou, Juxiang; Qiu, Shuang–Jian; Fan, Jia

doi:10.4161/auto.5.3.7658

Cited by 85 publications

(66 citation statements)

References 11 publications

(12 reference statements)

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“…39 Moreover, decreased autophagy in HCC correlates with a more aggressive cancer cell phenotype and poor prognosis. 21,40 Here we found that cannabinoid treatment reduces the growth of two different models of HCC subcutaneous xenografts in concert with decreased mTORC1 activation, enhanced AMPK phosphorylation and increased autophagy and apoptosis in those tumors. Moreover, knock down of the autophagic gene Atg5 as well as pharmacological inhibition of autophagy dramatically abolished the antitumoral activity of cannabinoids against subcutaneous HCC xenografts.…”

Section: Discussionmentioning

confidence: 96%

“…17 Although functional autophagy acts as a metabolic stress buffer, many lines of evidence support a role for autophagy in antagonizing cell survival and in promoting cell death and apoptosis. [18][19][20] Autophagy has an important role in cancer, and inhibition of this cellular process has been proposed to contribute to HCC progression, 21,22 and, therefore, it is a potentially very important target for liver cancer prevention and treatment.…”

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confidence: 99%

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Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

et al. 2011

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Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it is essential to search for new treatments to fight this disease. In this study, we investigated the effects of cannabinoids -a novel family of potential anticancer agents -on the growth of HCC. We found that D 9 -tetrahydrocannabinol (D 9 -THC, the main active component of Cannabis sativa) and JWH-015 (a cannabinoid receptor 2 (CB 2 ) cannabinoid receptor-selective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH-7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB 2 receptor. We also found that D 9 -THC-and JWH-015-induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serine-threonine kinase Akt/mammalian target of rapamycin C1 axis and adenosine monophosphate-activated kinase (AMPK) stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulin-activated kinase kinase b was responsible for cannabinoid-induced AMPK activation and autophagy. In vivo studies revealed that D 9 -THC and JWH-015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically of pharmacologically inhibited in those tumors. Moreover, cannabinoids were also able to inhibit tumor growth and ascites in an orthotopic model of HCC xenograft. Our findings may contribute to the design of new therapeutic strategies for the management of HCC. Hepatocellular carcinoma (HCC) is one of the most common solid tumors and the third leading cause of cancer-related death worldwide. 1 Its prognosis remains reserved, with a 5-year survival rate of o5%. 2 It is the most common cause of death in patients with cirrhosis 3 and, according to the World Health Organization, the incidence of HCC is expected to increase until 2030. The overall survival of patients with HCC has not significantly improved in the past two decades. Current treatments are only applicable at early stages of tumor development and include tumor resection, liver transplantation, chemoembolization and sorafenib administration. 4 However, approximately half of the patients suffer tumor recurrence. The most important mechanism of liver cancer progression is cell proliferation. Although in recent years several clinical trials have tested the efficacy of agents that selectively target important signaling pathways involved in the control of this process, no relevant improvement in the prognostic/survival of patients with HCC has been achieved so far, 5 and, therefore, it is necessary to identify novel therapeutic strategies for the management of HCC.Cannabinoids are lipid mediators originally isolated from the hemp plant Cannabis sativa that produce their effects by activating primarily two G-protein-coupled receptors: cannabinoid receptor 1 (CB 1 ), which is highly abundant in the b...

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

et al. 2011

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“…Such decreased cytoplasmic expression of BECN1 has been correlated with tumor progression in breast, ovarian, and cerebral neoplasms 39,46,47 and with a reduced survival rate in neoplasms of esophageal, colorectal, hepatocellular, and cerebral origin. [48][49][50][51] Liang et al 46 explained this immunohistochemical decline in cytoplasmic expression of the protein in terms of BECN1 inactivation and loss of its tumor suppressor functions. There have been, however, other tumors, including colorectal and gastric adenocarcinomas, in which progression appeared to be dependent upon an increased BECN1 expression.…”

Section: Discussionmentioning

confidence: 99%

Autophagy patterns and prognosis in uveal melanomas

et al. 2011

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Autophagy is a self-degradation mechanism by which cells recycle their own cytoplasmic constituents. It has been claimed that, under certain conditions, such a process may be associated with tumor progression. In this study, the autophagic activity was investigated in a series of 99 uveal melanomas after immunohistochemical staining for the autophagy-associated proteins MAP1LC3A and BECN1, most commonly known as LC3A and Beclin 1, respectively. These were assessed in parallel with the hypoxia-inducible factor 1a (HIF1A) and its downstream protein lactate dehydrogenase 5 (composed by five LDHA subunits). Increased autophagic reactivity, detected by MAP1LC3A or BECN1, was associated with intense pigmentation and tumor hypoxia. Uveal melanomas with extensive overexpression of BECN1 or those with underexpression of this protein were associated with the worst prognosis, but the former manifested metastases much earlier than the latter; only 58% of patients with extensive BECN1 overexpression were alive at 4 years, compared with 80% of patients with underexpressed patterns. It is concluded that autophagy is commonly upregulated in uveal melanomas, and may be associated with hypoxia and intense pigmentation. There is a strong association between extensive BECN1 overexpression and early metastases/poor prognosis, and between underexpression of this protein and late metastases/better prognosis.

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“…In particular, the aberrant expression of Beclin 1 (encoded by the human BECN1 gene) in many kinds of tumor tissues correlates with poor prognosis [74][75][76][77][78]. Beclin 1, the mammalian orthologue of yeast Atg6/vacuolar protein sorting (Vps)-30, plays an essential role in autophagy.…”

Section: Cancermentioning

confidence: 99%

Autophagy and human diseases

2013

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Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.

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Prognostic significance of Beclin 1-dependent apoptotic activity in hepatocellular carcinoma

Cited by 85 publications

References 11 publications

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy

Autophagy patterns and prognosis in uveal melanomas

Autophagy and human diseases

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