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Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G0/G1 cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality.

Solute carriers are membrane proteins that play an important role in cancer homeostasis by supplying cancer cells with essential building blocks and signaling molecules. Different types of membrane transporters were shown to be overexpressed in tumors in support of tumor growth and survival. Due to high affinity interaction with anticancer drugs they can also significantly contribute to the rapid chemoresistance. There is a limited number of studies on the role of solute carriers in reprogramming of cancer metabolism and signaling, especially in metastatic prostate cancer. Our study enabled us to establish the identity of the prostate cancer solute carrier that supports uptake of succinate and possibly similar energy rich metabolites from tumor microenvironment to promote an elevated energy metabolism of cancer cells. We demonstrated that prostate metastatic DU145 cells acquire Na+-dependent dycarboxylic acid carrier SLC13A3 but normal prostate PrEC cells do not express this protein. An important finding was that only at acidic pH 6.8 prostate cancer cells are capable of consuming exogenous succinate, while physiological pH 7.4 was not favorable for this process. Importantly, succinate transported by SLC13A3 not only accelerates the oxidative phosphorylation of prostate cancer mitochondria but it is also known to stabilize onco-factor HIF-1α. The HIF-involved signaling pathways have been linked to prostate tumorigenesis and chemoresistance and therefore, targeting these pathways by inhibiting cancer specific SLC13A3 has great potential for clinical benefit. In addition, the mechanism of succinate influx via SLC13A3 transporter in metastatic prostate cancer cells could also yield a novel metabolic onco-marker and has the potential to be used for imaging-based diagnostics to detect non-glycolytic tumors. Citation Format: Aigul Zhunussova, Zhanar Irgebayeva, Bhaswati Sen, Leah Friedman, Saniya Ossikbayeva, Sultan Tuleukhanov, Ari Brooks, Richard Sensenig, Zulfiya Orynbayeva. Tumor promoting activity of SLC13A3 in metastatic prostate cells. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B07.

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