Regulation of Multi-drug Resistance in hepatocellular carcinoma cells is TRPC6/Calcium Dependent

Abstract

Hepatocellular carcinoma (HCC) is notoriously refractory to chemotherapy because of its tendency to develop multi-drug resistance (MDR), whose various underlying mechanisms make it difficult to target. The calcium signalling pathway is associated with many cellular biological activities, and is also a critical player in cancer. However, its role in modulating tumour MDR remains unclear. In this study, stimulation by doxorubicin, hypoxia and ionizing radiation was used to induce MDR in HCC cells. A sustained aggregation of intracellular calcium was observed upon these stimuli, while inhibition of calcium signalling enhanced the cells’ sensitivity to various drugs by attenuating epithelial-mesenchymal transition (EMT), Hif1-α signalling and DNA damage repair. The effect of calcium signalling is mediated via transient receptor potential canonical 6 (TRPC6), a subtype of calcium-permeable channel. An in vivo xenograft model of HCC further confirmed that inhibiting TRPC6 enhanced the efficacy of doxorubicin. In addition, we deduced that STAT3 activation is a downstream signalling pathway in MDR. Collectively, this study demonstrated that the various mechanisms regulating MDR in HCC cells are calcium dependent through the TRPC6/calcium/STAT3 pathway. We propose that targeting TRPC6 in HCC may be a novel antineoplastic strategy, especially combined with chemotherapy.

Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

“…Indeed, global chelation of intracellular free Ca 2+ that attenuates increases in cytosolic free Ca 2+ , suppresses both EGF and hypoxia induced increases in the mesenchymal markers vimentin, N-cadherin and CD44 (Davis et al 2014a). Similar findings have now been reported in Huh7 and HepG2 hepatic cancer cell lines for EMT induced by doxorubicin (Wen et al 2016). It is also now clear that a major remodelling in calcium signalling and the expression of specific calcium permeable ion channels is a feature of EMT and some calcium permeable ion channels are important in the induction of expression of some proteins associated with the mesenchymal phenotype.…”

“…Consistent with a role for TRPM8 in the maintenance and/or induction of the mesenchymal phenotype in breast cancer cells, overexpression of TRPM8 in the more epithelial like MCF-7 cell line leads to EMT induction as indicated by down regulation of E-cadherin and induction of vimentin (Liu et al 2014). In Huh7 and HepG2 hepatic cancer cells, TRPC6 silencing attenuates changes in the expression of E-cadherin induced by doxorubicin suggesting that in the ability of TRPC6 silencing to increase sensitivity to doxorubicin through effects of resistance pathways may be due at least in part to effects on some aspects of EMT induction (Wen et al 2016).…”

Oncogenic role of the Notch pathway in primary liver cancer

“…Notch activation triggers epithelial-mesenchymal transformation (61). Several studies have revealed that a loss of the epithelial phenotype via epithelial-mesenchymal-transition promotes the acquisition of a stem-like phenotype and drug resistance (62)(63)(64). In addition, in patients with HCC an epithelial gene signature has been associated with sensitivity to the epidermal growth factor receptor inhibitors gefitinib and cetuximab (65).…”

Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies

“…Wen et al explored the roles of intracellular calcium on various MDR-relevant mechanisms in HCC cells 54. In their study, HCC cells were treated by stimulation with doxorubicin, hypoxia, and ionizing radiation, representing three models of MDR 54.…”