title: Tumor microenvironment promotes dicarboxylic acid carrier-mediated transport of succinate to fuel prostate cancer mitochondria.
abstract: Prostate cancer cells reprogram their metabolism, so that they support their elevated oxidative phosphorylation and promote a cancer friendly microenvironment. This work aimed to explore the mechanisms that cancer cells employ for fueling themselves with energy rich metabolites available in interstitial fluids. The mitochondria oxidative phosphorylation in metastatic prostate cancer DU145 cells and normal prostate epithelial PrEC cells were studied by high-resolution respirometry. An important finding was that prostate cancer cells at acidic pH 6.8 are capable of consuming exogenous succinate, while physiological pH 7.4 was not favorable for this process. Using specific inhibitors, it was demonstrated that succinate is transported in cancer cells by the mechanism of plasma membrane Na(+)-dependent dycarboxylic acid transporter NaDC3 (SLC13A3 gene). Although the level of expression of SLC13A3 was not significantly altered when maintaining cells in the medium with lower pH, the respirometric activity of cells under acidic condition was elevated in the presence of succinate. In contrast, normal prostate cells while expressing NaDC3 mRNA do not produce NaDC3 protein. The mechanism of succinate influx via NaDC3 in metastatic prostate cancer cells could yield a novel target for anti-cancer therapy and has the potential to be used for imaging-based diagnostics to detect non-glycolytic tumors.
authors.affiliation: Department of Surgery, Drexel University College of Medicine Philadelphia, PA, USA ; Al-Farabi Kazakh National University Almaty, Kazakhstan.
authors.forename: Aigul
authors.initials: A
authors.lastname: Zhunussova
authors.affiliation: Department of Surgery, Drexel University College of Medicine Philadelphia, PA, USA.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Sen
authors.affiliation: Department of Surgery, Drexel University College of Medicine Philadelphia, PA, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Friedman
authors.affiliation: Al-Farabi Kazakh National University Almaty, Kazakhstan.
authors.forename: Sultan
authors.initials: S
authors.lastname: Tuleukhanov
authors.affiliation: Department of Surgery, University of Pennsylvania Philadelphia, PA, USA.
authors.forename: Ari D
authors.initials: AD
authors.lastname: Brooks
authors.affiliation: Department of Surgery, University of Pennsylvania Philadelphia, PA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sensenig
authors.affiliation: Department of Surgery, Drexel University College of Medicine Philadelphia, PA, USA.
authors.forename: Zulfiya
authors.initials: Z
authors.lastname: Orynbayeva
keywords: Na+-dicarboxylate transporter; Prostate cancer; acidic tumor microenvironment; mitochondria oxidative phosphorylation; succinate