한빛사논문
- 조회758
고려대학교 의과대학
Dasom Kim1,2, Dongwha Min1,2, Joohee Kim3, Min Jung Kim3, Yerim Seo4, Byung Hwa Jung4,5, Seung‑Hae Kwon6, Hyunju Ro7, Seoee Lee7, Jason K. Sa2,8 and Ji‑Yun Lee1*
1Department of Pathology, Korea University College of Medicine, 73, Goryeodae‑Ro, Seongbuk‑Gu, Seoul 02841, South Korea.
2Department of Bio-medical Sciences, Korea University College of Medicine, Seoul, South Korea.
3Department of Biological Sciences, Sookmyung Women’s University, Seoul, South Korea.
4Center for Advanced Biomolecular Recognition, Korea Instiute of Science and Technology (KIST), Seoul 02792, Korea.
5Division of Bio‑Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, South Korea.
6Korea Basic Science Institute, Seoul Center, Seoul, South Korea.
7Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Korea.
*Correspondence: Ji‑Yun Lee
Abstract
Background
Oncogenic KRAS mutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-class KRAS-G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for other KRAS mutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies.
Methods
KRAS mutant, and wildtype NSCLC cells were used in vitro cell analyses. Cell viability, proliferation, and death were measured by MTT, cell counting, colony analyses, and annexin V staining for FACS. Cell tracker dyes were used to investigate cell morphology, which was examined by holotomograpy, and confocal microscopes. RNA sequencing was performed to identify key target molecule or pathway, which was confirmed by qRT-PCR, western blotting, and metabolite analyses by UHPLC-MS/MS. Zebrafish and mouse xenograft model were used for in vivo analysis.
Results
In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically in KRAS mutant /p53 wild type NSCLC cells.
Conclusion
These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/p53 wild type NSCLC cells.
논문정보
- Research article
- 2023년 12월 (BRIC 등록일 2023-12-14)
- 국내 연구진
- 생명과학 > 노화/암생물학
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