A PKM2 inhibitor induces apoptosis and autophagy through JAK2 in human oral squamous cell carcinoma cells

Jing-Ru Weng; Balraj Gopula; Po-Chen Chu; Jing-Lan Hu; Chia-Hsien Feng

doi:10.1016/j.cbi.2023.110538

A PKM2 inhibitor induces apoptosis and autophagy through JAK2 in human oral squamous cell carcinoma cells

Chem Biol Interact. 2023 Aug 1:380:110538. doi: 10.1016/j.cbi.2023.110538. Epub 2023 May 8.

Authors

Jing-Ru Weng¹, Balraj Gopula², Po-Chen Chu³, Jing-Lan Hu⁴, Chia-Hsien Feng⁵

Affiliations

¹ Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan; Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, 11042, Taiwan. Electronic address: jrweng@mail.nsysu.edu.tw.
² Drug Development Center, China Medical University, Taichung, 40402, Taiwan; Pharmacology & Chemical Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
³ Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung, 40604, Taiwan.
⁴ Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
⁵ Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.

PMID: 37164279
DOI: 10.1016/j.cbi.2023.110538

Abstract

The enzyme pyruvate kinase M2 (PKM2) is involved in glycolysis, which plays an important role in the regulation of tumor progression. In this study, we investigated the anti-tumor activity of N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)propiolamide (MTP), a PKM2 inhibitor, in oral squamous cell carcinoma (OSCC) cells. Our results showed that MTP inhibited cell growth with IC50 values of 0.59 μM and 0.78 μM in SCC2095 and HSC-3 OSCC cells, respectively. MTP induced caspase-dependent apoptosis, which was associated with the modulation of PKM2 and oncogenic biomarkers epidermal growth factor receptor and β-catenin. In addition, MTP increased the generation of reactive oxygen species (ROS) and modulated the expression of autophagic gene products, including LC3B-II and p62. Western blotting showed that MTP inhibited Janus kinase 2 (JAK2) signaling, and JAK2 overexpression partially reversed MTP-mediated cytotoxicity. Taken together, these data indicate the potential use of MTP as a therapeutic agent for OSCC.

Keywords: Apoptosis; Autophagy; JAK2; OSCC; PKM2; ROS.

MeSH terms

Apoptosis
Autophagy
Carcinoma, Squamous Cell* / metabolism
Cell Line, Tumor
Cell Proliferation
Head and Neck Neoplasms*
Humans
Janus Kinase 2 / metabolism
Mouth Neoplasms* / drug therapy
Mouth Neoplasms* / metabolism
Squamous Cell Carcinoma of Head and Neck

Substances

Janus Kinase 2
JAK2 protein, human