结直肠癌 (CRC) 是癌症相关死亡的主要原因之一，高达 80% 的晚期 CRC 病例表现出 p53 基因突变。不幸的是，针对突变型 p53 的新化合物的开发相当有限。脱氢表雄酮 (DHEA) 对多种癌症的抗癌作用已有报道。然而，DHEA 对携带野生型或突变型 p53 基因的 CRC 细胞的抑制作用仍存在争议。本研究重点揭示野生型或突变型p53基因存在下DHEA对CRC细胞肿瘤发生的抑制机制和作用。我们证明 DHEA 以剂量和时间依赖性方式导致 CRC 细胞死亡和细胞周期停滞。值得注意的是，无论 p53 基因状态如何，DHEA 对 CRC 细胞都表现出类似的抑制作用。进一步的研究表明，DHEA 诱导内质网 (ER) 应激并触发 PERK/eIF2/ATF4/CHOP UPR 信号通路激活自噬，随后发生细胞凋亡，这一点通过抑制 4-苯基丁酸（一种 ER 应激抑制剂）或敲低得到证实ATF4 或 CHOP。通过沉默 p53 / 或 p53-/- CRC 细胞中的 ATG5 基因，可以减弱 DHEA 诱导的细胞凋亡，这表明细胞凋亡的自噬调节。此外，DHEA 联合巴弗洛霉素 A1（自噬体降解阻断剂）治疗会导致 CRC 细胞中 ATF4、CHOP、DR5 和 p21 水平的积累，这意味着降解自噬机制调节这四种分子。 DHEA 通过抑制体内 CRC 肿瘤形成来证明其抑制作用。总而言之，我们提供了令人信服的证据，表明 DHEA 是 CRC 患者治疗的潜在候选治疗药物，无论通过 ER 应激-PERK-自噬-凋亡轴的 p53 状态如何。版权所有 © 2024 Nguyen, Ko, Tsai, Cheng, Tran, Doan, Hsiao,张、刘、洪、黄。

Colorectal cancer (CRC) is one of the primary contributors to cancer-related fatalities, with up to 80% of advanced CRC cases exhibiting mutations in the p53 gene. Unfortunately, the development of new compounds targeting mutant p53 is quite limited. The anticancer effects of Dehydroepiandrosterone (DHEA) on various cancers have been reported. However, the suppressive effect of DHEA on CRC cells harboring wild-type or mutant p53 gene remains controversial. This study emphasized revealing the suppressive mechanism and the effect of DHEA on CRC cell tumorigenesis in the presence of wild-type or mutant p53 gene. We demonstrate that DHEA causes CRC cell death and cell cycle arrest in a dose and time-dependent manner. Notably, DHEA exhibits similar inhibitory effects on CRC cells regardless of the p53 gene status. Further study reveals that DHEA induces endoplasmic reticulum (ER) stress and triggers PERK/eIF2/ATF4/CHOP UPR signaling pathway to activate autophagy followed by apoptosis, which was confirmed by suppression of 4-phenylbutyric acid (an ER stress inhibitor) or knockdown either ATF4 or CHOP. DHEA-induced apoptosis was attenuated by silencing ATG5 gene in either p53+/+ or p53-/- CRC cells, indicating autophagy regulation of apoptosis. Furthermore, DHEA treatment accompanied by bafilomycin A1 (a blocker of autophagosome degradation) leads to the accumulation of ATF4, CHOP, DR5, and p21 levels in CRC cells, implying that the degradative autophagy machinery regulates these four molecules. Consistently, DHEA demonstrates its inhibitory effect by suppressing CRC tumor formation in vivo. Altogether, we provide compelling evidence that DHEA is a potential therapeutic candidate for CRC patient treatment regardless of the p53 status through ER stress-PERK-autophagy-apoptosis axis.Copyright © 2024 Nguyen, Ko, Tsai, Cheng, Tran, Doan, Hsiao, Chang, Liu, Hong and Huang.