Cisplatin-Induced Cell Death In Mcf-7 Breast Cancer Cells: Roles Of (Delta) Nerbb2 And Ph Regulatory Ion Transporters Nhe1 And Nbcn1

We have shown that expression of a truncated constitutively active ErbB2 receptor (ΔNErbB2), which is associated with poor prognosis in breast cancer, greatly increased net acid extrusion in MCF‐7 breast cancer cells in a manner mediated by the Na + /H + exchanger NHE1 and the Na + ,HCO 3 − cotransporter NBCn1. Here, we explore the roles of NHE1 and NBCn1 in cisplatin‐induced cancer cell death. In both vector‐ and ΔNErbB2 cells, cisplatin treatment (25 μM, 18 h) induced cleavage of caspase‐9,‐7, PARP, and fodrin (a calpain substrate), and cysteine cathepsin release, all in a manner slightly augmented by NHE1 inhibition. Expression of the anti‐apoptotic Bcl‐2 protein was markedly reduced in ΔNErbB2‐ compared to vector cells. Cisplatin treatment increased p53‐ and PUMA levels in both cell types, and reduced the number of autophagic vesicles and increased p62 levels, most markedly in ΔNErbB2 cells. This reduction of autophagic flux was not significantly affected by inhibition of NHE1 or NBCn1. Finally, cisplatin treatment elicited marked perinuclear accumulation of NBCn1, but not of NHE1, and reduced the protein levels of both full length‐ and ΔN‐ErbB2. In conclusion , cisplatin treatment of MCF‐7 cells activates several death mechanisms, some of which are further exacerbated by NHE1 inhibition in agreement with previous findings that NHE1 inhibition sensitizes MCF‐7‐ΔNErbB2 cells to cisplatin‐induced death. Funding: Danish Cancer Society, Danish Research Council