title: 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.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of General Surgery, Ningbo Medical Treatment Center Lihuili Hospital, Ningbo, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Enjiang
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wei
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, Henan Province People's Hospital, Henan, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xue
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Guogang
authors.initials: G
authors.lastname: Li
authors.affiliation: Center for Immunology and Microbial Disease,Albany Medical College, ME-205 47 New Scotland Ave., MC-151, Albany, New York, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Gong
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, PR China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.|Collaborative Innovation Center for Cancer Medicine, Zhejiang University, Hangzhou, PR China.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Liang
mesh_terms: D002118:Calcium / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D002118:Calcium