Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self‐renew and often escape therapy. The key metabolic sensor AMP‐activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib‐induced cell death. We report that sorafenib‐resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib‐induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A‐769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia‐inducible factor HIF‐1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem‐like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC.
Highlights
Cancer continues to be the second leading cause of death in Western countries
To investigate whether long-term sorafenib treatment induced cancer stem cell (CSC) differentiation in Hepatocellular carcinoma (HCC) cultures, we analysed the expression of the cell membrane protein CD133, which was recently identified as a stem cell marker in HCC (Castelli et al, 2017)
As CD133 was poorly detected in HepG2 cells, we examined the embryonic protein alpha fetoprotein (ΑFP), which has been proposed as a stem cell marker and is clearly detected in HepG2 cells
Summary
Cancer continues to be the second leading cause of death in Western countries. More than 2 million new cases of cancer and 610 000 cancer deaths are predicted to occur only in the United States during 2018 (Siegel et al, 2018). The multikinase inhibitor sorafenib has been the only approved standard treatment for patients with advanced HCC (Kudo, 2017), albeit it only extends life expectancy by 2–3 months (Cheng et al, 2009; Llovet et al, 2008; Tovoli et al, 2018). This can be attributed to the acquisition of resistance, predominantly due to the upregulation of certain survival pathways that may cover up the death signals induced by sorafenib (Zhu et al, 2017). The elucidation of the underlying mechanisms of evasive resistance is required to overcome unwanted tumour recurrence and, to improve the beneficial effects of chemotherapy
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