NHC Key Lab of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200080, People's Republic of China; Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200080, People's Republic of China.
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200080, People's Republic of China; Department of Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China.
Cancer Lett. 2020 Apr 28;476:34-47. doi: 10.1016/j.canlet.2020.02.009. Epub 2020 Feb 13.
Succinate is an important intermediate of the tricarboxylic acid cycle. Recently discovered roles of succinate demonstrate its involvement in immunity and cancer biology; however, the precise underlying mechanisms of its involvement in these additional roles remain to be determined. In the present study, succinate dehydrogenase (SDH) B was decreased in uterine endometrial cancer cells (UECC) under negative regulation of estrogen. This decrease was the result of lower expression levels of ubiquitin C (UBC), which was associated with the activation of peroxisome proliferator-activated receptor gamma and specificity protein 1. The decreased levels of SDHB resulted in the accumulation of succinate in UECC, and thus, a decrease in the production of fumaric acid. Succinate downregulated voltage-gated potassium channel subfamily Q member 1 (KCNQ1) levels by activating serum/glucocorticoid regulated kinase 1 and promoted the growth of UECC in vitro and in vivo. Treatment with melatonin restricted estrogen/UBC/SDHB-induced succinate accumulation and upregulated expression of KCNQ1 and reduced the succinate-mediated growth of UECC in vitro and in vivo. Furthermore, overexpression of melatonin receptor 1B amplified the inhibitory effects of melatonin on succinate-mediated UECC growth. Together, the data in the present study suggest that melatonin suppresses UECC progression by inhibiting estrogen/UBC/SDHB-induced succinate accumulation. The present study provides a scientific basis for potential therapeutic strategies and targets in UEC, particularly for patients with abnormally low levels of SDHB.
琥珀酸是三羧酸循环的重要中间产物。最近发现的琥珀酸的作用表明其参与了免疫和癌症生物学；然而，其在这些额外作用中的参与的确切潜在机制仍有待确定。在本研究中，琥珀酸脱氢酶（SDH）B 在雌激素负调控下在子宫子宫内膜癌细胞（UECC）中减少。这种减少是由于泛素 C（UBC）的表达水平降低所致，这与过氧化物酶体增殖物激活受体γ和特异性蛋白 1 的激活有关。SDHB 水平的降低导致 UECC 中琥珀酸的积累，从而导致富马酸的产生减少。琥珀酸通过激活血清/糖皮质激素调节激酶 1 下调电压门控钾通道亚家族 Q 成员 1（KCNQ1）的水平，并促进 UECC 在体外和体内的生长。褪黑素治疗限制了雌激素/UBC/SDHB 诱导的琥珀酸积累，并上调了 KCNQ1 的表达，减少了 UECC 在体外和体内的琥珀酸介导的生长。此外，褪黑素受体 1B 的过表达放大了褪黑素对琥珀酸介导的 UECC 生长的抑制作用。综上所述，本研究数据表明，褪黑素通过抑制雌激素/UBC/SDHB 诱导的琥珀酸积累来抑制 UECC 的进展。本研究为 UEC 的潜在治疗策略和靶点提供了科学依据，特别是对于 SDHB 水平异常低的患者。
