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Roles of NHE1 and NBCn1 in pH‐regulation and chemotherapy resistance in MCF‐7 breast cancer cells expressing constitutively active ErbB2
Author(s) -
Lauritzen Gitte,
Dybboe Rie,
Boedtkjer Ebbe,
Aalkjaer Christian,
Nylandsted Jesper,
Pedersen Stine Falsig
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.656.1
Altered pH‐regulation plays important roles in cancer progression yet the mechanisms are poorly understood. Here, we investigate the effects of a constitutively active ErbB2 receptor (ΔNErbB2) on the Na + /H + exchanger NHE1 and the Na + ,HCO 3 − cotransporter NBCn1 in MCF‐7 breast cancer cells. ΔNErbB2 expression elicited marked morphological changes, increased the expression of NBCn1, and altered the localization of both transporters. The pH i recovery rate after an acid load increased by 50% after ΔNErbB2 expression, due to contributions from both NHE1 and NBCn1. NHE1 inhibition (EIPA) or ‐knockdown sensitized ΔNErbB2‐expressing cells to cisplatin‐induced programmed cell death (PCD) in a caspase‐, cathepsin‐, and ROS‐dependent manner. EIPA augmented cisplatin‐induced caspase‐9 and ‐7 activity and lysosomal cysteine cathepsin release. In contrast, inhibition of NBCn1 reduced cathepsin release and had no net effect on cisplatin‐induced PCD. Cisplatin had little effect on initial pH i but induced NHE1 dimerization, and appeared to inhibit autophagy. In conclusion, NHE1 and NBCn1 are regulated by ΔNErbB2 and serve different functions in pH‐regulation and survival in MCF‐7 cells. Financial support: Novo Nordisk Foundation, Danish Cancer Society, Danish National Research Council.