PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263.
PMCA2 overexpression in some breast cancers suggests that this calcium pump isoform may play a role in breast pathophysiology. To investigate PMCA2 as a potential drug target for breast cancer therapy, we assessed the functional consequence of PMCA2 silencing on cell death pathways and calcium signals in the basal-like MDA-MB-231 breast cancer cell line. Silencing PMCA2 expression alone has no effect on MDA-MB-231 cell viability, however, PMCA2 silencing promotes calcium-induced cell death initiated with the calcium ionophore ionomycin. Assessment of cytoplasmic calcium responses generated with various agents including ionomycin demonstrates that in MDA-MB-231 cells, PMCA2 does not play a major role in shaping global calcium signals. We also examined the ability of PMCA2 silencing to modulate caspase-dependent cell death triggered by a Bcl-2 inhibitor that is in clinical development for the treatment of various cancers, ABT-263 (Navitoclax). Despite the lack of effect on global calcium responses, PMCA2 silencing augmented Bcl-2 inhibitor (ABT-263)-mediated MDA-MB-231 breast cancer cell death. These studies provide evidence that PMCA2 inhibitors could sensitize PMCA2-positive breast cancers to cell death initiators that work through mechanisms involving the Bcl-2 survival pathway.
School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
Merril
M
Curry
School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia.
Sarah J
SJ
Roberts-Thomson
School of Pharmacy, The University of Queensland, Brisbane, Queensland, 4072, Australia; Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia; Translational Research Institute, Brisbane, Queensland, Australia. Electronic address: gregm@uq.edu.au.
Gregory R
GR
Monteith
D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D061207:Calcium Ionophores; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D015759:Ionomycin; D020169:Caspases; D053499:Plasma Membrane Calcium-Transporting ATPases; C506958:ATP2B2 protein, human; D002118:Calcium; C528561:navitoclax
ABT-263; Breast cancer; Calcium; Cell death; Ionomycin; PMCA2