Abstract 479: Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells

Abstract

Abstract Pyruvate kinase M2 (PKM2) is a key enzyme involved in the regulation of glycolysis. Although PKM2 is overexpressed in various tumor tissues, its functional role in cancer chemotherapy remains unclear. In this study, we investigated the anticancer activity of novel PKM2 inhibitors in the regulation of cell metabolism and its associated pathways in prostate cancer cells. To evaluate the molecular basis of specific PKM2 inhibitors, the interactions of compounds 3h and 3K with the PKM2 protein were assessed via molecular docking. We found that, compared to compound 3K, compound 3h exhibited a higher binding affinity for PKM2. Moreover, compound 3h significantly inhibited the pyruvate kinase activity and PKM2 expression. Cytotoxicity and colony formation assays revealed the potent anticancer activity of compound 3h against LNCaP cells. Compound 3h significantly increased the apoptotic and autophagic cell death in LNCaP cells. In addition, compound 3h induced AMPK activation along with the inhibition of mTOR/p70S6K pathway. Furthermore, compound 3h significantly inhibited glycolysis and mitochondrial respiration, as determined by analyzing extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) production. Our results revealed that compound 3h caused apoptotic and autophagic cell death by inhibiting cancer cell metabolism in LNCaP cells. Therefore, blocking glycolytic pathways using specific PKM2 inhibitors can be used to target cancer cell metabolism in PKM2-overexpressed prostate cancer cells. Citation Format: Chunxue Jiang, Tian Zheng, HwaYoung Cha, Hyung Sik Kim. Novel specific PKM2 inhibitor, compound 3h, induces apoptotic and autophagic cell death through Akt/mTOR signaling pathway in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 479.