Research Paper|Volume 12, Issue 18|pp 17930—17947

Modulating redox homeostasis and cellular reprogramming through inhibited methylenetetrahydrofolate dehydrogenase 2 enzymatic activities in lung cancer

Chun-Hao Chan^1,², Chia-Yu Wu^3,⁴, Navneet Kumar Dubey^1,², Hong-Jian Wei², Jui-Hua Lu^1,², Samantha Mao², Joy Liang², Yu-Hsuan Liang⁵, Hsin-Chung Cheng^1,⁶, Win-Ping Deng^1,^2,⁷

¹School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
²Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
³Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Medical University Hospital, Taipei 11031, Taiwan
⁴School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
⁵Department of Materials Science and Engineering, National Taiwan University, Taipei 10617, Taiwan
⁶Department of Dentistry, Taipei Medical University Hospital, Taipei 110131, Taiwan
⁷Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan

Received: November 22, 2019Accepted: May 27, 2020Published: August 6, 2020

https://doi.org/10.18632/aging.103471

Copyright: © 2020 Chan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Recent reports have indicated the role of highly expressed methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) enzyme in cancers, showing poor survival; however, detailed mechanistic insight of metabolic functions of MTHFD2 have not been well-defined. Therefore, we aimed to examine the metabolic functions and cellular reprograming potential of MTHFD2 in lung cancer (LCa). In this study, we initially confirmed the expression levels of MTHFD2 in LCa not only in tissue and Oncomine^TM database, but also at molecular levels. Further, we reprogrammed metabolic activities in these cells through MTHFD2 gene knockdown via lentiviral transduction, and assessed their viability, transformation and self-renewal ability. In vivo tumorigenicity was also evaluated in NOD/SCID mice. Results showed that MTHFD2 was highly expressed in stage-dependent LCa tissues as well in cell lines, A549, H1299 and H441. Cellular viability, transformation and self-renewal abilities were significantly inhibited in MTHFD2-knockdown LCa cell lines. These cells also showed suppressed tumor-initiating ability and reduced tumor size compared to vector controls. Under low oxygen tension, MTHFD2-knockdown groups showed no significant increase in sphere formation, and hence the stemness. Conclusively, the suppressed levels of MTHFD2 is essential for cellular metabolic reprogramming leading to inhibited LCa growth and tumor aggressiveness.