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Novel Specific Pyruvate Kinase M2 Inhibitor, Compound 3h, Induces Apoptosis and Autophagy through Suppressing Akt/mTOR Signaling Pathway in LNCaP Cellsopen access

Authors
Jiang, C[Jiang, Chunxue]Zhao, X[Zhao, Xiaodi]Jeong, T[Jeong, Taejoo]Kang, JY[Kang, Ju Young]Park, JH[Park, Jae Hyeon]Kim, IS[Kim, In Su]Kim, HS[Kim, Hyung Sik]
Issue Date
Jan-2023
Publisher
MDPI
Keywords
PKM2 inhibitors; cell metabolism; prostate cancer; apoptosis; glycolysis
Citation
CANCERS, v.15, no.1
Indexed
SCIE
SCOPUS
Journal Title
CANCERS
Volume
15
Number
1
URI
https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/102607
DOI
10.3390/cancers15010265
ISSN
2072-6694
Abstract
Simple Summary Prostate cancer is a serious threat to male health worldwide; however, chemotherapy remains an urgent problem because of resistance and insensitivity to androgen-deprivation therapy. Therefore, discovering novel molecules and chemotherapy can provide a new strategy. Pyruvate kinase M2 (PKM2) is not only a vital enzyme in regulating cancer glycolysis, but is also a transcription that regulates gene expression through nuclear translocation, so the targeting PKM2 can be a promising therapy for prostate cancer. In this experiment, we found a novel specific PKM2 inhibitor-compound 3h-and conducted molecular and cellular experiments to evaluate its anticancer effect. Our results indicated that proliferation of LNCaP cells can be inhibited by compound 3h through inducing apoptosis and autophagy, and inhibiting glycolysis and mitochondria respiration. Therefore, our results provide a new way of developing novel chemotherapy for prostate cancer. 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 unexplored. In this study, we investigated the anticancer activity of a new PKM2 inhibitor, compound 3h, through the cell metabolism and associated signaling 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 the mTOR/p70S6K pathway. Furthermore, compound 3h significantly inhibited glycolysis and mitochondrial respiration, as determined by analyzing the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) production. Our results revealed that compound 3h caused apoptotic and autophagic cell death in LNCaP cells by inhibiting cancer cell metabolism. Therefore, blocking glycolytic pathways using specific PKM2 inhibitors can target cancer cell metabolism in PKM2-overexpressed prostate cancer cells.
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