Active Estrogen-Succinate Metabolism Promotes Heme Accumulation and Increases the Proliferative and Invasive Potential of Endometrial Cancer Cells

Jia-Jing Lu; Xing Zhang; Ayitila Abudukeyoumu; Zhen-Zhen Lai; Ding-Yu Hou; Jiang-Nan Wu; Xiang Tao; Ming-Qing Li; Xiao-Yong Zhu; Feng Xie

doi:10.3390/biom13071097

Active Estrogen-Succinate Metabolism Promotes Heme Accumulation and Increases the Proliferative and Invasive Potential of Endometrial Cancer Cells

Biomolecules. 2023 Jul 10;13(7):1097. doi: 10.3390/biom13071097.

Authors

Jia-Jing Lu^{1

2}, Xing Zhang², Ayitila Abudukeyoumu³, Zhen-Zhen Lai², Ding-Yu Hou⁴, Jiang-Nan Wu⁵, Xiang Tao⁶, Ming-Qing Li^{2

7}, Xiao-Yong Zhu^{4

7}, Feng Xie^{1

7}

Affiliations

¹ Medical Center of Diagnosis and Treatment for Cervical and Intrauterine Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China.
² Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200080, China.
³ Department of Gynecology, Shanghai Jiading Maternal Child Health Hospital, Shanghai 201800, China.
⁴ Department of Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
⁵ Clinical Epidemiology, Clinical Research Center, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200080, China.
⁶ Department of Pathology, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200011, China.
⁷ Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China.

Abstract

Uterine endometrial cancer (UEC) is an estrogen-related tumor. Succinate and heme metabolism play important roles in the progression of multiple tumors. However, the relationship between estrogen, succinate, and heme metabolism and related regulatory mechanisms remain largely unknown. In this study, we observed that the expression of aminolevulinate delta synthase 1 (ALAS1) and solute carrier family member 38 (SLC25A38) in UEC tissues is significantly higher than that in normal tissues. Further analysis showed that estrogen and succinate increased the expression of ALAS1 and SLC25A38 in uterine endometrial cancer cells (UECC), and the administration of succinate upregulated the level of the estrogen receptor (ER). Silencing nuclear receptor coactivator 1 (NCOA1) reversed the effects of estrogen and succinate via downregulation of ALAS1 expression. Additionally, exposure of UECC to heme increased cell viability and invasiveness, while silencing the NCOA1 gene weakened this effect. These findings revealed that estrogen and succinate can synergistically increase the expression of ALAS1 and SLC25A38 via the ERβ/NCOA1 axis, promoting heme accumulation and increasing the proliferative and invasive potential of UECC.

Keywords: NCOA1; estrogen; heme; succinate; uterine endometrial cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminolevulinic Acid
Endometrial Neoplasms* / metabolism
Estrogens / pharmacology
Female
Heme
Humans
Receptors, Estrogen
Succinic Acid*

Substances

Succinic Acid
Heme
Estrogens
Receptors, Estrogen
Aminolevulinic Acid

Grants and funding

This work was supported by the Program of National Natural Science Foundation of China (NSFC, 82072872, 82071624, 81871143, 92057119, and 31970798), the Program for Zhuoxue of Fudan University (JIF157602), and the Support Project for Original Personalized Research of Fudan University (IDF157014/002).