Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
# Xianlong Ling and Lei Wen contribute equally to this study.
Multidrug resistance (MDR) is a major obstacle of cancer chemotherapy. This study aimed to investigate the role of mitochondrial translocation of telomerase (hTERT) in MDR of human hepatocellular carcinoma (HCC) cells. In this study, three HCC cell lines (SK-Hep1/CDDP1 cells, SK-Hep1/CDDP2 cells and SK-Hep1/CDDP3 cells) with differential resistance index (RI) to cisplatin (CDDP) were induced by pulse treatment of SK-Hep1 (human hepatocellular cell line) with CDDP in vitro. The RI of SK-Hep1/CDDP1 cells, SK-Hep1/CDDP2 cells and SK-Hep1/CDDP3 cells was 5.14, 8.66, and 14.25, respectively, and all the cell lines showed cross-resistance to Doxorubicin (DOX) and 5-Fuorouracil (5-FU). The apoptosis rates in drug-resistant cells were significantly reduced. Cell cycle analysis revealed the ratio of drug-resistant cells in G2/M and S phases increased, while that in G1 phase decreased. Immunofluorescence staining and Western blot assay demonstrated, with the gradual elevation in RI, increasing hTERT translocated from the nuclei to the mitochondria, while real-time PCR indicated the shortening of telomere length in drug-resistant cells under the chemotherapeutic stress and the reduction of damaged mtDNA with the increase in RI. Furthermore, JC-1 staining also indicated the reduction of mitochondrial membrane potential in drug-resistant cells. The mitochondrial translocation of hTERT increases in multidrug-resistant cells and exerts protective effect on mitochondrial function. Drug-resistant tumor cells escape from apoptosis through hTERT-mediated mitochondrial protection. Mitochondrial translocation of hTERT may serve as an underlying mechanism of MDR.
Keywords: Telomerase, Telomere, Mitochondria, Multidrug resistance