Loading...
Journal Title
Keywords
Readers/Advisors
Sheikh, M. Saeed
Journal Title
Term and Year
Fall 2025
Publication Date
2025-08-28
Book Title
Publication Volume
Publication Issue
Publication Begin
Publication End
Number of pages
Files
Research Projects
Organizational Units
Journal Issue
Abstract
Lung cancer is the leading cause of cancer-related deaths; thus, newer therapeutic approaches are urgently needed. In recent years, several studies have shown that tumors, including lung cancers, undergo metabolic rewiring for continuous growth and survival. This reprogramming, influenced by oncogenic mutations and nutrients, is believed to promote cancer progression. Consequently, therapeutic approaches to target cancer metabolism is a viable approach. Here we report that CB-839 (glutaminase-1 inhibitor) and metformin (anti-diabetic drug) induce metabolic stress and also inhibit human lung cancer cell growth.
The effects of these agents were tested in three human lung cancer cell lines, namely H460, A549, and H1299. Our results revealed that these agents did not considerably affect cell cycle regulation. However, they induced cell death in H460 and A549 cells through upregulation and stabilization of Death Receptor 5 (DR5) protein. These agents did not considerably upregulate DR5 in H1299 cells. However, H1299 cells activated autophagy instead, a survival mechanism triggered under metabolic stress. Inhibition of autophagy using 3-methyladenine in H1299 cells resulted in metabolic stress-mediated upregulation of DR5 and cell death, suggesting autophagy plays a protective role in these cells.
Our findings show that these three lung cancer lines exhibit variable sensitivity to CB-839 and metformin. In H460 and A549 cells, which harbor mutant K-Ras, these agents promote apoptosis by activating the DR5-dependent extrinsic pathway. By contrast, in wild-type K-Rass carrying H1299 cells, autophagy is activated with minimal effect on DR5 regulation. Therefore, we also investigated whether the status of K-Ras affected the sensitivity of these cells to metabolic stress. Accordingly, we utilized a pan-K-Ras inhibitor and noted that inhibition of mutant K-Ras in H460 and A549 cells decreased sensitivity to CB-839 and metformin. These findings led us to conclude mutant K-Ras to be one of the underlying reasons for the increased susceptibility of H460 and A549 lung cancer cells to CB-839 and metformin-induced growth inhibition.
Collectively, our findings suggest that CB-839 and Metformin have the potential to become components of novel therapeutic strategies for managing lung cancer.
Citation
DOI
Description
Accessibility Statement
If this SOAR repository item is not accessible to you (e.g. able to be used in the context of a disability), please email libsuppt@upstate.edu.