Koyanagi Takahiro, Saga Yasushi, Takahashi Yoshifumi, Tamura Kohei, Suizu Eri, Takahashi Suzuyo, Taneichi Akiyo, Takei Yuji, Mizukami Hiroaki, Fujiwara Hiroyuki
Department of Obstetrics and Gynecology, School of Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Japan.
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke City, Tochigi, Japan.
Cancer Rep (Hoboken). 2025 Apr;8(4):e70202. doi: 10.1002/cnr2.70202.
Progesterone rapidly induces ovarian cancer cell death through non-genomic actions mediated by the membrane progesterone receptor (mPR).
We investigated the combined effects of progesterone and SN38, an active metabolite of irinotecan, on ovarian cancer cells.
mPR-positive and PR-negative ovarian cancer cell lines were utilized in experiments. Tumor cells were exposed to SN38 or cisplatin for 48 h following exposure to progesterone for 30 min. The viable cell counts were measured using a colorimetric assay and the expression of topoisomerase I (TOPO-I), the direct target of SN38, was observed with or without exposure to progesterone. Moreover, we investigated the relationship between several types of programmed cell death and the SN38 sensitivity enhancement effect of progesterone using specific cell death inhibitors. The chemosensitivity to SN38 was 8.7- to 26.0-fold higher with the administration of progesterone than that without (p < 0.01), but not to cisplatin in ovarian cancer cells. Progesterone suppressed the expression of TOPO-I mRNA by less than 50% (p < 0.01). Furthermore, among various programmed cell death inhibitors, only the ferroptosis inhibitor attenuated the progesterone-induced SN38 chemosensitivity enhancement effect.
Progesterone increased sensitivity to SN38 by suppressing TOPO-I expression and inducing ferroptosis. The combination of progesterone and irinotecan could be a novel treatment modality for ovarian cancer.
孕酮通过膜孕酮受体（mPR）介导的非基因组作用迅速诱导卵巢癌细胞死亡。
我们研究了孕酮与伊立替康的活性代谢产物SN38联合对卵巢癌细胞的作用。
实验采用mPR阳性和PR阴性的卵巢癌细胞系。肿瘤细胞在暴露于孕酮30分钟后，再暴露于SN38或顺铂48小时。使用比色法测定活细胞计数，并观察有无孕酮暴露时SN38的直接靶点拓扑异构酶I（TOPO-I）的表达。此外，我们使用特异性细胞死亡抑制剂研究了几种程序性细胞死亡类型与孕酮增强SN38敏感性效应之间的关系。在卵巢癌细胞中，给予孕酮时对SN38的化学敏感性比未给予时高8.7至26.0倍（p<0.01），但对顺铂无此作用。孕酮使TOPO-I mRNA的表达抑制不到50%（p<0.01）。此外，在各种程序性细胞死亡抑制剂中，只有铁死亡抑制剂减弱了孕酮诱导的SN38化学敏感性增强效应。
孕酮通过抑制TOPO-I表达和诱导铁死亡增加对SN38的敏感性。孕酮与伊立替康联合可能是一种新的卵巢癌治疗方式。
