Targeting TR4 nuclear receptor with antagonist bexarotene increases docetaxel sensitivity to better suppress the metastatic castration-resistant prostate cancer progression.

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men in America, and there are no curative options for metastatic castration-resistant prostate cancer (mCRPC). Docetaxel (DTX) has been used as a standard chemotherapy for the mCRPC. However, resistance to DTX is a significant clinical problem as half of patients fail to respond to therapy. The TR4 nuclear receptor has been reported to play an important role in PCa progression, however, its linkage to the DTX resistance remains unclear. Here we found that TR4 was upregulated after DTX chemotherapy in the mCRPC cells and patients, and TR4 expression is correlated with DTX sensitivity with a higher level conferring chemo-resistance. Targeting TR4 with an antagonist bexarotene (Bex, a derivative of retinoid) suppressed the TR4 transactivation with increased DTX chemo-sensitivity. Mechanism dissection studies revealed that TR4 might alter the DTX chemo-sensitivity via modulating the TR4/lincRNA-p21/HIF-1α/VEGF-A signaling. Together, these results suggest that targeting this newly identified TR4/lincRNA-p21/HIF-1α/VEGF-A signaling with Bex, an FDA-approved drug, may increase the DTX chemo-sensitivity to better suppress the mCRPC progression.

• Authors: Linyi Hu, Yin Sun, Jie Luo, Xiang He, Meihua Ye, Gonghui Li, Yong Zhang, Jian Bai, Dahong Zhang, Chawnshang Chang
• Journal: Oncogene (Oncogene) Vol. 39 Issue 9 Pg. 1891-1903 (02 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 31748715 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• NR2C2 protein, human
• Receptors, Steroid
• Receptors, Thyroid Hormone
• Docetaxel
• Bexarotene

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Bexarotene (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Docetaxel (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, secondary)
• Receptors, Steroid (antagonists & inhibitors)
• Receptors, Thyroid Hormone (antagonists & inhibitors)
• Tumor Cells, Cultured