Targeting mitochondrial transcription factor A sensitizes pancreatic cancer cell to gemcitabine

Background: The survival of pancreatic cancer cells, particularly cancer stem cells which are responsible for tumor relapse, depends on mitochondrial function. Mitochondrial transcription factor A (TFAM) is critical for the regulation of mitochondrial DNA and thus mitochondrial function. However, the possible involvement of TFAM in pancreatic cancer is unknown.Methods: Human samples were obtained from pancreatic cancers and their adjacent tissues; human pancreatic cell lines were cultured in RPMI1640 medium. TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry, ELISA, and reverse transcription polymerase chain reaction (RT-PCR). The effect of TFAM on cell growth, migration, colony formation and apoptosis were evaluated. Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.Results: The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts. Consistently, TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells. There was no difference on TFAM level be-tween gemcitabine-sensitive and resistant pancreatic cancer cells. Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells. TFAM inhibition enhanced gemcitabine's cytotoxicity and suppressed growth, anchorage-independent colony formation and survival of gemcitabine-resistant pan-creatic cancer cells. Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochon-drial dysfunction and energy crisis followed by oxidative stress. The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.Conclusions: TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.(c) 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.