Enhanced mitochondrial fission promotes chemosensitivity via SHP-1 activity in triple-negative breast cancer

Vollständiger Abstract

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Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype with high chemoresistance and poor survival rates. While mitochondrial dynamics, fission and fusion, are implicated in chemoresistance, their precise roles remain largely unexplored. This study investigates how cytoplasmic phosphatases SHP-1 and SHP-2 regulate chemotherapeutic response in TNBC cells with altered mitochondrial dynamics. Methods We utilized click beetle green luciferase-expressing SUM149 and SUM159 TNBC cells engineered to stably express mitochondrial dynamics modulators (PISD, Drp1, MFN2). SHP-1/2 activity was further manipulated using either the inhibitor NSC87877 or stable shRNA knockdown, confirmed by qRT-PCR and Western Blotting. Cell growth and cytotoxicity were evaluated through bioluminescence imaging and drug assays using doxorubicin, paclitaxel, and salinomycin. Results We show that SUM149 and SUM159 TNBC cells engineered to exhibit enhanced mitochondrial fission via increased PISD and Drp1 expression are more sensitive to doxorubicin and salinomycin, but not paclitaxel. SHP-1/2 inhibition attenuated doxorubicin and salinomycin sensitivity specifically in mitochondrial fission-enriched cells, with minimal effects in fusion-enriched cells and no effect on paclitaxel response. Notably, only SHP-1 knockdown reduced drug sensitivity in cells with enhanced mitochondrial fission, highlighting SHP-1 as a key regulator of chemoresistance. Conversely, enhanced mitochondrial fusion conferred resistance to cytotoxic agents. Conclusions Our in vitro findings demonstrate that mitochondrial fission sensitizes TNBC cells to certain chemotherapeutics, and that SHP-1 critically regulates this response. This newly identified mechanism links mitochondrial dynamics to chemotherapeutic sensitivity, offering a potential pathway to overcome TNBC chemoresistance through targeted therapies.