Differential Effects of Estrogen Receptor Alpha and Beta on Endogenous Ligands of Peroxisome Proliferator-Activated Receptor Gamma in Papillary Thyroid Cancer.

Shucai Yang,Jason Yk Chan,Zhongqin Gong,Jing Du,Wei Wei,Lingbin Xue,Minghui Wei,C Andrew Van Hasselt,Shuqi Qiu,Nelson Tang,Zhimin Liu,Yang Zhang,Xianhai Zeng,Michael Cf Tong,George G Chen,Alexander C Vlantis

doi:10.3389/fendo.2021.708248

Abstract

PurposeThe inhibition of estrogen receptor alpha (ERα) or the activation of ERβ can inhibit papillary thyroid cancer (PTC), but the precise mechanism is not known. We aimed to explore the role of ERα and ERβ on the production of endogenous peroxisome proliferator-activated receptor gamma (PPARγ) ligands in PTC.Methods2 PTC cell lines, 32 pairs of PTC tissues and matched normal thyroid tissues were used in this study. The levels of endogenous PPARγ ligands 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), and15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) were measured by ELISA.ResultsThe levels of PGJ2 and 15(S)-HETE were significantly reduced in PTC, but 13(S)-HODE was not changed. Activation of ERα or inhibition of ERβ significantly downregulated the production of PGJ2, 15(S)-HETE and 13(S)-HODE, whereas inhibition of ERα or activation of ERβ markedly upregulated the production of these three ligands. Application of endogenous PPARγ ligands inhibited growth, induced apoptosis of cancer cells, and promoted the efficacy of chemotherapy.ConclusionThe levels of endogenous PPARγ ligands PGJ2 and 15(S)-HETE are significantly decreased in PTC. The inhibition of ERα or activation of ERβ can inhibit PTC by stimulating the production of endogenous PPARγ ligands to induce apoptosis in cancer cells.

Highlights

There is increasing evidence indicating that activation of peroxisome proliferator-activated receptor gamma (PPARg) by its ligands can inhibit the growth of thyroid cancer, likely via multi-mechanisms including stimulation of the anti-tumor immune system, induction of cancer cell differentiation, increase of radioiodine uptake in thyroid cancer cells, cell cycle arrest, and promotion of apoptosis of cancer cells [1,2,3,4,5,6,7,8,9,10,11,12]
The concentration of 13(S)-HODE was decreased in papillary thyroid cancer (PTC) tumor tissues compared with that in the non-tumor tissues but the difference did not reach a significant point (p>0.05, data not shown)
In order to assess whether the production of endogenous PPARg ligands, PGJ2, 15(S)-HETE and 13(S)-HODE, could be regulated by ERa and ERb, PPT (ERa agonist), DPN (ERb agonist), MPP (ERa antagonist) and PHTPP (ERb antagonist) were employed in this study

Summary

Introduction

There is increasing evidence indicating that activation of peroxisome proliferator-activated receptor gamma (PPARg) by its ligands can inhibit the growth of thyroid cancer, likely via multi-mechanisms including stimulation of the anti-tumor immune system, induction of cancer cell differentiation, increase of radioiodine uptake in thyroid cancer cells, cell cycle arrest, and promotion of apoptosis of cancer cells [1,2,3,4,5,6,7,8,9,10,11,12]. Some publications have challenged the safety of synthetic PPARg ligands that are currently employed as anti-tumor agents in most studies. The administration of synthetic PPARg ligands is known to produce some significant side-effects including an increased risk of bladder cancer and cardiovascular diseases [3, 20, 21]. These adverse effects have limited the therapeutic application of synthetic PPARg ligands

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