Peroxiredoxin 3 maintains the survival of endometrial cancer stem cells by regulating oxidative stress.

In-Sung Song,Jung Mi Byun,Jin Han,Dae Hoon Jeong,Young Jin Seo,Ki Tae Kim,Yu Jeong Jeong,Young Nanm Kim,Sung-Wuk Jang

doi:10.18632/oncotarget.21580

In-Sung Song, Jung Mi Byun + Show 7 more

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https://doi.org/10.18632/oncotarget.21580

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Abstract

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.

Highlights

Endometrial cancer (EC) is commonly diagnosed at an early stage, as a tumor originating in the endometrium
We evaluated the mitochondrial function of endometrial Cancer stem cell (CSC) (CD133+) compared to that of nonCSCs (CD133−) isolated using a CD133 antibody (Figure 1)
We assessed the level of the fructose 1,6-biphosphatase (FBP1) gluconeogenic enzyme, which has been shown to contribute to the characteristics of CSCs in basal-like breast cancer [28] and found that the level of FBP1 was higher in CSCs than in non-CSCs (Figure 1I)

Summary

Introduction

Endometrial cancer (EC) is commonly diagnosed at an early stage, as a tumor originating in the endometrium. Cases with high-grade aggressive and metastatic ECs show poor clinical outcomes because of the lack of targets required for targeted therapy. Drugs such as cisplatin, carboplatin, paclitaxel, and doxorubicin have been used in single-agent regimens for EC treatment, and showed a response rate ranging from 21% to 36% in patients with EC [8]. Carboplatin, paclitaxel, and doxorubicin have been used in single-agent regimens for EC treatment, and showed a response rate ranging from 21% to 36% in patients with EC [8] Together, these data indicate the need for new therapies based on a better understanding of the molecular mechanisms underlying EC, its recurrence, and its metastasis

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