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.
Highlights
The development of antineoplastic drugs has made great progress
transient receptor potential (TRP) canonical 6 (TRPC6) inhibition could reverse doxorubicin-induced epithelial-mesenchymal transition (EMT) (Fig. 5c), block hypoxia-induced hypoxia-inducible factor1-α (Hif1-α) expression (Fig. 5d) and inhibit DNA damage repair at 2 h after ionizing radiation (Fig. 5e). These results demonstrated that the calcium channel TRPC6 plays a vital role in the sustained aggregation of [Ca2+]c under various stimuli, which in turn is directly involved in regulating EMT, Hif1-α signalling and DNA damage repair
Previous studies aiming to overcome multi-drug resistance (MDR) or chemo-resistance were restricted to single-target research, which usually resulted in limited curative efficacy
Summary
The development of antineoplastic drugs has made great progress. their limited curative efficacy still remains a clinical obstacle, which is mainly ascribed to multi-drug resistance (MDR), induced by conventional drugs and by new “targeted” drugs[1,2]. Numerous studies have revealed that MDR is associated with overexpression of certain drug efflux pumps[5], epithelial mesenchymal transition (EMT)[6,7], the hypoxia-inducible factor1-α (Hif1-α ) signalling pathway[8], DNA damage repair[1,9,10,11], autophagy induction[12] and epigenetic regulation[13]. Several mechanisms govern MDR induction, among which drug efflux pump, EMT, Hif1-α signalling and DNA damage repair play vital roles in the chemo-resistance of HCC16,18–20. Some studies demonstrated that MDR-relevant mechanisms of EMT, hypoxia-induced Hif1-α signalling pathway and DNA damage repair are closely related to intracellular calcium. In this study, we explored the roles of intracellular calcium on various MDR relevant mechanisms, and further investigated its upstream TRP calcium channel and the common downstream regulator in HCC cells
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