Kim Dong-Hwan, Kim Dong Joon, Park Seong-Jun, Jang Won-Jun, Jeong Chul-Ho
College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
Department of Microbiology, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea.
J Microbiol Biotechnol. 2025 Apr 10;35:e2412032. doi: 10.4014/jmb.2412.12032.
Pancreatic cancer, a leading cause of cancer-related deaths, is characterized by increased dependence on glutamine metabolism. Telaglenastat (CB-839), a glutaminase (GLS) inhibitor targets glutamine metabolism; however, its efficacy as monotherapy is limited owing to metabolic adaptations. In this study, we demonstrated that CB-839 effectively inhibited cell growth in pancreatic cancer cells, but activated the general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) signaling pathway. ATF4 knockdown reduced glutamine transporter alanine, serine, and cysteine transporter 2 (ASCT2) expression, glutamine uptake, and cell viability under glutamine deprivation-recovery conditions, confirming its protective role in mitigating glutamine-related metabolic stress. Notably, the combination of CB-839 and the ASCT2 inhibitor V-9302 demonstrated a synergistic effect, significantly suppressing pancreatic cancer cell survival. These findings highlight ATF4 and ASCT2 as crucial therapeutic targets and indicate that dual inhibition of GLS and ASCT2 may enhance treatment outcomes for pancreatic cancer.
胰腺癌是癌症相关死亡的主要原因之一，其特点是对谷氨酰胺代谢的依赖性增加。特拉格列司他（CB - 839）是一种谷氨酰胺酶（GLS）抑制剂，作用于谷氨酰胺代谢；然而，由于代谢适应性，其作为单一疗法的疗效有限。在本研究中，我们证明CB - 839能有效抑制胰腺癌细胞的生长，但激活了一般控制非抑制性2（GCN2）-激活转录因子4（ATF4）信号通路。在谷氨酰胺剥夺 - 恢复条件下，敲低ATF4可降低谷氨酰胺转运体丙氨酸、丝氨酸和半胱氨酸转运体2（ASCT2）的表达、谷氨酰胺摄取及细胞活力，证实了其在减轻谷氨酰胺相关代谢应激中的保护作用。值得注意的是，CB - 839与ASCT2抑制剂V - 9302联合使用显示出协同效应，显著抑制胰腺癌细胞存活。这些发现突出了ATF4和ASCT2作为关键治疗靶点，并表明双重抑制GLS和ASCT2可能提高胰腺癌的治疗效果。
