Targeting Galectin-1 Impairs Castration-Resistant Prostate Cancer Progression and Invasion.

Abstract

Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC.Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells.Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1-binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivoConclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. Clin Cancer Res; 24(17); 4319-31. ©2018 AACR.

• Authors: Tsung-Chieh Shih, Ruiwu Liu, Chun-Te Wu, Xiaocen Li, Wenwu Xiao, Xiaojun Deng, Sophie Kiss, Ting Wang, Xiao-Jia Chen, Randy Carney, Hsing-Jien Kung, Yong Duan, Paramita M Ghosh, Kit S Lam
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 17 Pg. 4319-4331 (09 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29666302 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• AR protein, human
• Androgen Antagonists
• Galectin 1
• Receptors, Androgen

Topics

• Androgen Antagonists (pharmacology)
• Animals
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Disease Progression
• Galectin 1 (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Neoplasm Invasiveness (genetics, pathology)
• Neoplasm Metastasis
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Androgen (genetics)
• Tissue Array Analysis
• Xenograft Model Antitumor Assays