Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma

Villanueva, Augusto; Chiang, Derek Y.; Newell, Pippa; Peix, Judit; Thung, Swan N.; Alsinet, Clara; Tovar, Victoria; Roayaie, Sasan; Mínguez, Beatriz; Solé, Manel; Battiston, Carlo; Laarhoven, Stijn van; Fiel, M. Isabel; Feo, Analisa Di; Hoshida, Yujin; Yea, Steven; Toffanin, Sara; Ramos, Alex H.; Martignetti, John A.; Mazzaferro, Vincenzo; Bruix, Jordi; Waxman, Samuel; Schwartz, Myron; Meyerson, Matthew; Friedman, Scott L.; Llovet, Josep M.

doi:10.1053/j.gastro.2008.08.008

Cited by 663 publications

(604 citation statements)

References 43 publications

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“…To note, it has been recently described that mTOR signaling has a critical role in the pathogenesis of HCC and that mTOR inhibitors have antineoplastic activity in experimental models of HCC. 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.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2011

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“…Hyperactivation of mTORC1 have further been established for RCC cell lines and tumors as well as for various NET cell lines and animal models (Chan et al, 2010), and in B50% of hepatocellular carcinomas (Villanueva et al, 2008). Together, the observed exaggerated activation of mTORC1 in these LKB1/ AMPK/TSC-associated lesions suggests that mTORC1 would serve an effective target for therapy to treat these cancerous and hamartomatous lesions.…”

Section: Hyperactive Mtorc1 In Lkb1/ampk/tsc-associated Lesionsmentioning

confidence: 95%

“…Somatic inactivating mutations in the tumor suppressor gene PTEN are frequently detected in glioblastomas, melanomas, and in prostate and endometrial cancers (Sansal and Sellers, 2004). Loss of PTEN expression has been observed in sporadic hepatocellular carcinomas (Villanueva et al, 2008).…”

Section: Nf1mentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…It may also have a role in leiomyosarcomas oncogenic processes, as it is the kinase responsible for AKT1 phosphorylation on serine 473, thus allowing its full activity. 16 RICTOR genomic gains have indeed been linked to tumor recurrence in hepatocellular carcinoma, 34 and its overexpression in glioma cell lines lead to increased anchorage-independent growth and motility. 35 Thus this study allowed us to demonstrate, in a large series of sarcomas with complex genomics, the frequent loss of PTEN expression in these tumors, presumably by a 'gene-dose effect' mechanism.…”

Section: Components Of the Mtor Complexes: Rictor Expressionmentioning

confidence: 99%

From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas

et al. 2012

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Over the past decade, comprehensive genomic studies demonstrated that leiomyosarcomas and most of the tumors previously labeled as 'malignant fibrous histiocytomas' share complex karyotypes and genomic profiles, and can be referred to as 'sarcomas with complex genomics'. We recently reported a series of 160 sarcomas with complex genomics such as leiomyosarcomas, myxofibrosarcomas, pleomorphic liposarcomas/ rhabdomyosarcomas and undifferentiated pleomorphic sarcomas. These tumors present with a frequent loss of chromosome 10 region encompassing the tumor suppressor gene PTEN. In the present study, we assessed PTEN genomic level and protein expression in this large series of sarcomas with complex genomics, as well as activation of downstream pathways. PTEN partial genomic loss was observed in only 46% of tumors, especially in well-differentiated leiomyosarcomas, whereas up to 68% of these tumors demonstrate a loss of protein expression on western blot analysis. Specific discrepancies in PTEN immunohistochemical results suggested bias in this latter technique. PTEN mutations were rare, with only 4 point mutations in the 65 samples studied. Subsequent activation of AKT and mTOR pathways was only observed in 2 out of 3 of PTEN-deleted tumors. On the other hand, RICTOR, a major component of the mTOR complex 2, was significantly overexpressed in welldifferentiated leiomyosarcomas. These results, confirmed on tissue micro-array immunohistochemical analysis of 459 sarcomas, could suggest a link between RICTOR overexpression and leiomyosarcomas oncogenesis. As therapeutics directed against the mTOR pathway are assessed in sarcomas, RICTOR overexpression in sarcomas and its links to therapeutic response need to be assessed.

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Pivotal Role of mTOR Signaling in Hepatocellular Carcinoma

Cited by 663 publications

References 43 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

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas and pleomorphic sarcomas

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