Hong Seongwoo, Lee Rami, Park Gyun Seok, Han Sumin, Shin Juhyun, Lee Yoon-Mi, Nah Seung-Yeol, Oh Jae-Wook
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
Ginsentology Research Laboratory, Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea.
Curr Issues Mol Biol. 2024 Sep 27;46(10):10880-10895. doi: 10.3390/cimb46100646.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising chemotherapeutic agent because of its selective apoptotic action on cancer cells. However, resistance to TRAIL-induced apoptosis remains a challenge in many cancers. The gintonin-enriched extract fraction (GEF) has diverse pharmacological benefits. We explored the combined efficacy of GEF and TRAIL in inducing apoptosis in human renal cell carcinoma (RCC) cells. The effect of GEF treatment on the viability, clonogenic potential, wound healing, and TRAIL-induced apoptotic signaling of RCC cells was studied in vitro. Our investigation revealed that GEF pre-treatment sensitized RCC cells to TRAIL-induced apoptosis, as evidenced by DNA fragmentation and cell proliferation, colony formation, and migration inhibition. This sensitization was linked to the upregulation of death receptors 4 and 5 and alterations in apoptotic protein expression, notably, the decreased expression of the Mu-2-related death-inducing gene, a novel anti-apoptotic protein. Our findings underscore the necessity of caspase activation for GEF/TRAIL-induced apoptosis using the pan-caspase inhibitor Z-VAD-FMK. This study demonstrates that GEF sensitizes human RCC cells to TRAIL-induced apoptosis by upregulating DR4/5 and modulating apoptotic protein expression. These findings suggest a promising strategy for overcoming TRAIL resistance in cancer therapy and highlight the potential of GEF as a valuable adjunct to TRAIL-based treatments.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）因其对癌细胞具有选择性凋亡作用，是一种很有前景的化疗药物。然而，对TRAIL诱导的凋亡产生抗性在许多癌症中仍然是一个挑战。富含人参皂苷的提取物组分（GEF）具有多种药理益处。我们探究了GEF与TRAIL联合诱导人肾细胞癌（RCC）细胞凋亡的疗效。在体外研究了GEF处理对RCC细胞活力、克隆形成潜力、伤口愈合及TRAIL诱导的凋亡信号传导的影响。我们的研究表明，GEF预处理使RCC细胞对TRAIL诱导的凋亡敏感，DNA片段化、细胞增殖、集落形成及迁移抑制证明了这一点。这种敏感性与死亡受体4和5的上调以及凋亡蛋白表达的改变有关，特别是与一种新型抗凋亡蛋白——Mu-2相关死亡诱导基因表达的降低有关。我们的研究结果强调了使用泛半胱天冬酶抑制剂Z-VAD-FMK激活半胱天冬酶对GEF/TRAIL诱导凋亡的必要性。本研究表明，GEF通过上调DR4/5和调节凋亡蛋白表达，使人RCC细胞对TRAIL诱导的凋亡敏感。这些发现提示了一种在癌症治疗中克服TRAIL抗性的有前景的策略，并突出了GEF作为基于TRAIL治疗的有价值辅助药物的潜力。
