Peroxiredoxin 3 maintains the survival of endometrial cancer stem cells by regulating oxidative stress
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In-Sung Song1, Yu Jeong Jeong1, Young Jin Seo2, Jung Mi Byun2, Young Nanm Kim2, Dae Hoon Jeong2, Jin Han3, Ki Tae Kim2,* and Sung-Wuk Jang1,*
1Department of Biomedical Sciences, College of Medicine, Ulsan University, Asan Medical Center, Seoul, Republic of Korea
2Department of Obstetrics & Gynecology, Paik Institute for Clinical Research, Busan Paik Hospital, Inje University, Busan, Republic of Korea
3National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Republic of Korea
*These authors have contributed equally to this work
Ki Tae Kim, email: [email protected]
Sung-Wuk Jang, email: [email protected]
Keywords: peroxiredoxin 3, endometrial cancer, cancer stem cells, oxidative stress, mitochondria
Received: June 23, 2017 Accepted: September 08, 2017 Published: October 06, 2017
Cancer stem cell (CSC)-targeted therapy could reduce tumor growth, recurrence, and metastasis in endometrial cancer (EC). The mitochondria of CSCs have been recently found to be an important target for cancer treatment, but the mitochondrial features of CSCs and their regulators, which maintain mitochondrial function, remain unclear. Here, we investigated the mitochondrial properties of CSCs, and identified specific targets for eliminating CSCs in EC. We found that endometrial CSCs displayed higher mitochondrial membrane potential, Ca2+, reactive oxygen species, ATP levels, and oxygen consumption rates than non-CSCs. Further, we also verified that mitochondrial peroxiredoxin 3 (Prx3) was upregulated, and that it contributed to the survival of CSCs in EC. The knockdown of the Prx3 gene resulted not only in decreased sphere formation, but also reduced the viability of endometrial CSCs, by causing mitochondrial dysfunction. Furthermore, we found that the forkhead box protein M1 (FoxM1), an important transcriptional factor, is overexpressed in patients with EC. FoxM1 expression correlates with elevated Prx3 expression levels, in agreement with the tumorigenic ability of Prx3 in endometrial CSCs. Taken together, our findings indicate that human endometrial CSCs have enhanced mitochondrial function compared to that of endometrial tumor cells. Endometrial CSCs show increased expression of the mitochondrial Prx3, which is required for the maintenance of mitochondrial function and survival, and is induced by FoxM1. Based on our findings, we believe that these proteins might represent valuable therapeutic targets and could provide new insights into the development of new therapeutic strategies for patients with endometrial cancer.
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