Drp1-Dependent Mitochondrial Fission is Involved in Adriamycin Resistance in Gastric Cancer Cells: A Perspective from the BATF2/p53/ERK Regulatory Axis.

Drug resistance affects the therapeutic effect of adriamycin on gastric cancer (GC). Therefore, this study aimed to explore the mechanism of basic leucine zipper (bZIP) transcription factor ATF-like 2 (BATF2) on adriamycin resistant (ADR) in GC cells and the involvement of mitochondrial fission in this process. A BATF2-overexpressed lentiviral vector was transfected into SGC7901/ADR cells, and effects of elevated BATF2 expression on the sensitivity of SGC7901 cells to adriamycin was observed by Transwell assays. The changes in mitochondrial morphology, fission marker expressions, and ATP levels after BATF2 overexpression were evaluated using Mito-Tracker Red staining, laser confocal, western blot and a detection kit. A ERK agonist was added to observe the effect of BATF2 overexpression on ERK phosphorylation levels. Co-immunoprecipitation (Co-IP) was used to confirm protein interactions between BATF2 and p53. PFT-α was adopted to observe the effects of p53 inhibition on BATF2-mediated ADR. In vitro experiments revealed that BATF2 overexpression restored drug sensitivity to adriamycin in SGC7901 cells and inhibited Drp1-dependent mitochondrial fission. Meanwhile, BATF2 overexpression also achieved the reversal of ADR in GC cells by inhibiting the phosphorylation level of ERK. P53 is an upstream regulator of ERK and interacts with BATF2 at the protein level. The suppression of p53 can significantly attenuated the inhibition of BATF2 overexpression on ADR, ERK phosphorylation, and Drp1-dependent mitochondrial fission in SGC7901/ADR cells. To conclude, BATF2 targets p53 and reverses drug resistance to adriamycin in GC cells by inhibiting ERK phosphorylation levels and downstream Drp1-dependent mitochondrial fission.