Joshi Himani, Huang Ying, Sheikh M Saeed
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York.
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York.
J Pharmacol Exp Ther. 2025 Jun;392(6):103598. doi: 10.1016/j.jpet.2025.103598. Epub 2025 May 3.
Lung cancer remains one of the major causes of cancer-related mortality. Thus, newer therapeutic approaches are urgently needed. Because cancer is a metabolic disease, lung cancer cells have also rewired their metabolism to gain growth advantage and support survival. Therefore, the use of metabolic stress-inducing agents as a therapeutic strategy for lung cancer is an attractive idea. In this study, we have investigated the anticancer potential of CB-839 and metformin. CB-839, a selective glutaminase-1 inhibitor, creates glutamine-deficient conditions, and metformin is an antidiabetic drug. We report that CB-839 and metformin induce metabolic stress and inhibit growth of human lung cancer cells. Of note, lung cancer cells that harbor mutant K-Ras are more sensitive to these agents compared to cells with wild-type K-Ras status. In the K-Ras mutant cells, these agents induce cell death partly, via death receptor 5 (DR5)-dependent extrinsic pathway. However, in the lung cancer cells harboring wild-type K-Ras, these agents activate autophagy without significant effect on DR5 regulation. Pretreatment of K-Ras wild-type cells with autophagy inhibitor improves the anticancer potential of these agents coupled with activation of DR5-dependent pathway. Our results further show that the growth inhibitory effects of these agents appear to be linked to the mutant K-Ras status because pan-K-Ras inhibitor that inhibits the mutant K-Ras proteins blunted the growth inhibitory effects of these agents in cells harboring mutant K-Ras. Collectively, our results provide valuable new insights into exploiting the metabolic rewiring of lung cancer cells by using metabolic stress-inducing drugs as an important therapeutic approach. SIGNIFICANCE STATEMENT: Anticancer potential of CB-839 and metformin is investigated in lung cancer. These agents induce cell death partly, via death receptor 5-dependent pathway, and a relationship with K-Ras status of lung cancer cells is noted. Lung cancer cells with mutant K-Ras are more sensitive compared to cells with wild-type K-Ras. Autophagy inhibition of K-Ras wild-type cells improves the anticancer potential. This study provides new insights into exploiting the metabolic rewiring of lung cancer cells as an important therapeutic strategy.
肺癌仍然是癌症相关死亡的主要原因之一。因此，迫切需要更新的治疗方法。由于癌症是一种代谢性疾病，肺癌细胞也重新调整了其代谢以获得生长优势并维持生存。因此，使用代谢应激诱导剂作为肺癌的治疗策略是一个有吸引力的想法。在本研究中，我们研究了CB - 839和二甲双胍的抗癌潜力。CB - 839是一种选择性谷氨酰胺酶 - 1抑制剂，可造成谷氨酰胺缺乏的条件，而二甲双胍是一种抗糖尿病药物。我们报告称，CB - 839和二甲双胍可诱导代谢应激并抑制人肺癌细胞的生长。值得注意的是，与具有野生型K - Ras状态的细胞相比，携带突变型K - Ras的肺癌细胞对这些药物更敏感。在K - Ras突变细胞中，这些药物部分通过死亡受体5（DR5）依赖性外源性途径诱导细胞死亡。然而，在携带野生型K - Ras的肺癌细胞中，这些药物激活自噬，而对DR5调节没有显著影响。用自噬抑制剂预处理K - Ras野生型细胞可提高这些药物的抗癌潜力，并激活DR5依赖性途径。我们的结果进一步表明，这些药物的生长抑制作用似乎与突变型K - Ras状态有关，因为抑制突变型K - Ras蛋白的泛K - Ras抑制剂减弱了这些药物对携带突变型K - Ras细胞的生长抑制作用。总的来说，我们的结果为利用代谢应激诱导药物作为一种重要的治疗方法来利用肺癌细胞的代谢重编程提供了有价值的新见解。意义声明：研究了CB - 839和二甲双胍在肺癌中的抗癌潜力。这些药物部分通过死亡受体5依赖性途径诱导细胞死亡，并注意到与肺癌细胞K - Ras状态的关系。与具有野生型K - Ras的细胞相比，具有突变型K - Ras的肺癌细胞更敏感。对K - Ras野生型细胞的自噬抑制可提高抗癌潜力。本研究为利用肺癌细胞的代谢重编程作为一种重要的治疗策略提供了新见解。
