Medical & Surgical Urology
Open Access
ISSN: 2168-9857
+44-77-2385-9429
ISSN: 2168-9857
+44-77-2385-9429
Ki Cheong Park, Seung Won Kim, Jeong Yong Jeon , Kyung Seok Han and Jae-Ho Cheong
Posters-Accepted Abstracts: Med Surg Urol
Selection pressure generated by the evolving tumor metabolic microenvironment, particularly glucose deprivation results in the emergence of sub-clones that display enhanced capabilities of survival. In vitro, these cells showed much higher antiapoptotic capability than their parental counterparts. In this study, we demonstrate the potential mechanisms by which these selected kidney cancer cells avoid Ca2+-induced apoptosis during glucose deprivation. The induction of plasma membrane Ca2+ ATPase (PMCA) is mainly responsible for the transport of cytoplasmic Ca2+ to the extracellular space while B-cell lymphoma 2 (BCL2) induction by calcium/calmodulin dependent protein kinase 2 alpha (CaMK2α) signaling plays key roles in the blocking of Ca2+-dependent apoptosis. Of note, all of these effects are governed by the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, which transcriptionally co-regulates PMCA and CaMK2α expression thereby circumventing cytoplasmic Ca2+overload induced apoptosis upon prolonged glucose deprivation. Combined treatment with 2-Deoxy-D-glucose (2DG), a metabolic inhibitor, mimicking glucose deprivation condition in mouse xenograft models and caloxin, a specific inhibitor of PMCA significantly reduced tumor growth compared to the tumors of untreated control animals and those treated with the metabolic inhibitor alone. The current study provides compelling evidence that PGC1α is a key regulator of anti-apoptosis in metabolic stress-selected cells by inducing PMCA and CaMK2α allowing survival in glucose-deprived conditions.