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

Abstract

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...

Anti-proliferative effects of anandamide in human hepatocellular carcinoma cells

“…Similar antitumor effects have recently been reported in a variety of cancers including breast cancer, prostate cancer, C6 glioma cells, colorectal cancer, gastric cancer and cholangiocarcinoma (7)(8)(9)(10)(11)(12)(13). In HCC, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main active component of Cannabis sativa and JWH-015 (a cannabinoid receptor 2 (CB2)-selective agonist) were suggested to demonstrate inhibitory effects on growth both in vitro and in vivo (22). Concordant with these findings, the data in the present study demonstrate that the endogenous cannabinoid AEA reduced the viability of HCC cells.…”

Autophagy in colorectal cancer: An important switch from physiology to pathology

“…This suggests that only a fraction of cancer patients may benefit from the administration of autophagy inhibitors. Along similar lines, autophagy has been shown to underlie, at least in part, the therapeutic activity of some anticancer regimens [118,119] . Autophagy promotes cancer cell survival under stressful conditions or nutrient deprivation and thus may contribute to chemoresistance.…”

The endocannabinoid system in normal and pathological brain ageing

“…Cannabinoids have been previously implicated in inducing autophagy in various cancer cell types: glioma [171] hepatocellular carcinoma [172], pancreatic adenocarcinoma [173], and these effects are at least, in part, dependent on the CB1 receptor. We have found an altered autophagosomal and lysosomal turnover in Cnr1 -/2 mice (A. Piyanova 2012, unpublished results), suggesting a regulatory role for endocannabinoid signalling in autophagy also in non-cancerous tissues.…”