Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia.
Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Front Endocrinol (Lausanne). 2022 Oct 3;13:941834. doi: 10.3389/fendo.2022.941834. eCollection 2022.
Although ovarian sex steroids could have protective roles against colorectal cancer (CRC) in women, little is currently known about their potential anti-tumorigenic effects in men. Hence, this study measured the therapeutic effects of 17β-oestradiol (E2) and/or progesterone (P4) against azoxymethane-induced CRC in male mice that were divided into (n = 10 mice/group): negative (NC) and positive (PC) controls, E2 (580 µg/Kg/day; five times/week) and P4 (2.9 mg/Kg/day; five times/week) monotherapies, and concurrent (EP) and sequential (E/P) co-therapy groups. Both hormones were injected intraperitoneally to the designated groups for four consecutive weeks. Similar treatment protocols with E2 (10 nM) and/or P4 (20 nM) were also used in the SW480 and SW620 human male CRC cell lines. The PC group showed abundant colonic tumours alongside increased colonic tissue testosterone levels and androgen (AR) and oestrogen (ERα) receptors, whereas E2 and P4 levels with ERβ and progesterone receptor (PGR) decreased significantly compared with the NC group. E2 and P4 monotherapies equally increased ERβ/PGR with p21/Cytochrome-C/Caspase-3, reduced testosterone levels, inhibited ERα/AR and CCND1/survivin and promoted apoptosis relative to the PC group. Both co-therapy protocols also revealed better anti-cancer effects with enhanced modulation of colonic sex steroid hormones and their receptors, with E/P the most prominent protocol. , E/P regimen showed the highest increases in the numbers of SW480 (2.1-fold) and SW620 (3.5-fold) cells in Sub-G1 phase of cell cycle. The E/P co-therapy also disclosed the lowest percentages of viable SW480 cells (2.8-fold), whilst both co-therapy protocols equally showed the greatest SW620 apoptotic cell numbers (5.2-fold) relative to untreated cells. Moreover, both co-therapy regimens revealed maximal inhibitions of cell cycle inducers, cell survival markers, and AR/ERα alongside the highest expression of cell cycle suppressors, pro-apoptotic molecules, and ERβ/PGR in both cell lines. In conclusion, CRC was associated with abnormal levels of colonic sex steroid hormones alongside aberrant protein expression of their receptors. While the anti-cancer effects of E2 and P4 monotherapies were equal, their combination protocols showed boosted tumoricidal actions against CRC in males, possibly by promoting ERβ and PGR-mediated androgen deprivation together with inhibition of ERα-regulated oncogenic pathways.
虽然卵巢性激素可能对女性的结直肠癌（CRC）具有保护作用，但目前对于其在男性中的潜在抗肿瘤作用知之甚少。因此，本研究测量了 17β-雌二醇（E2）和/或孕酮（P4）对雄性小鼠中氧化偶氮甲烷诱导的 CRC 的治疗作用，这些雄性小鼠被分为（每组 n = 10 只小鼠）：阴性（NC）和阳性（PC）对照组、E2（580μg/Kg/天；每周 5 次）和 P4（2.9mg/Kg/天；每周 5 次）单疗法组，以及同时（EP）和序贯（E/P）联合治疗组。两种激素均通过腹腔注射至指定组中，连续 4 周。还使用了具有 E2（10 nM）和/或 P4（20 nM）的类似治疗方案，用于 SW480 和 SW620 人男性 CRC 细胞系。PC 组表现出丰富的结肠肿瘤，同时结肠组织中的睾丸激素水平以及雄激素（AR）和雌激素（ERα）受体增加，而与 NC 组相比，E2 和 P4 水平以及 ERβ 和孕激素受体（PGR）明显降低。E2 和 P4 单疗法同样增加了 ERβ/PGR 与 p21/细胞色素 C/半胱天冬酶-3，降低了睾丸激素水平，抑制了 ERα/AR 和 CCND1/生存素，并促进了与 PC 组相比的细胞凋亡。两种联合治疗方案还显示出更好的抗癌作用，通过增强结肠性激素及其受体的调节作用，E/P 方案最为突出。E/P 方案显示 SW480（2.1 倍）和 SW620（3.5 倍）细胞周期中 Sub-G1 期的细胞数量增加最多。E/P 联合治疗还显示 SW480 细胞的存活百分比最低（2.8 倍），而两种联合治疗方案在未处理的细胞中同样显示出 SW620 细胞凋亡数量最多（5.2 倍）。此外，两种联合治疗方案均显示出对细胞周期诱导物、细胞存活标志物和 AR/ERα 的最大抑制作用，以及对两种细胞系中细胞周期抑制剂、促凋亡分子和 ERβ/PGR 的最高表达。总之，CRC 与结肠性激素水平异常以及其受体的异常蛋白表达有关。虽然 E2 和 P4 单疗法的抗癌作用相当，但它们的联合方案显示出对男性 CRC 的更强抗肿瘤作用，可能通过促进 ERβ 和 PGR 介导的雄激素剥夺以及抑制 ERα 调节的致癌途径来实现。
