抑制LGALS1可透過降低能量代謝來增強AR表達的前列腺癌細胞對ENZ敏感性

李亞哲¹、沈正煌¹、賴雅燕¹、陳瑞傑²

1.嘉義基督教醫院泌尿外科, 2.嘉義大學生化科技學系

Inhibition of LGALS1 Enhances ENZ Sensitivity in AR-Expressing Prostate Cancer Cells by Suppressing Energy Metabolism

Ya-Che Lee¹, Cheng-Huang Shen¹, Ya-Yan Lai ¹, Jui-Chieh Chen²

¹Department of Urology, Chiayi Christian Hospital, Chiayi, Taiwan

²Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan

Purpose:

Prostate cancer is the second leading cause of cancer death in men. In the early stages of prostate cancer, the standard treatments are surgical removal or radiation therapy. For advanced-stage patients, the standard treatment is androgen deprivation therapy (ADT) combined with radiation therapy. However, some patients may develop metastatic castration-resistant prostate cancer (mCRPC), leading to treatment failure. In such cases, enzalutamide (ENZ), an androgen receptor (AR) antagonist, is often used to improve treatment effectiveness. Certain patients still develop resistance to ENZ, highlighting the urgent need for the development of new treatment options. Galectins (LGALSs) are potential targets for cancer therapy as they play important roles in tumor processes such as apoptosis, cell adhesion, and metastasis.

Materials and Methods:

We downloaded RNA sequencing datasets from ENZ-resistant and parental prostate cancer cells in the Gene Expression Omnibus (GEO) database and reanalyzed them to investigate LGALS expression. The relationship between AR and LGALS was investigated using an AR-positive 22Rv1 and an AR-negative PC3 cell line. Genes were knocked out using CRISPR-Cas9 and their impact on cell growth, ENZ sensitivity, cell cycle, and cell motility was assessed using MTT assays, flow cytometry, wound healing, and Transwell. Finally, the molecular mechanisms affected by gene knockout were comprehensively analyzed using RNA sequencing (RNA-Seq) and bioinformatics tools.

Results:

The GEO database showed that the expression of LGALS1 is highest in ENZ-resistant prostate cancer cells. Results from qPCR and Western blot analyses indicated that PC3 cells exhibited significantly higher levels of LGALS1 expression compared to 22Rv1 cells. Compared to 22Rv1 cells, the MTT assay results demonstrated that PC3 cells exhibited a significant resistance to ENZ. Knockout of LGALS1 significantly increased the sensitivity of 22Rv1 cells to ENZ but did not affect the sensitivity of PC3 cells to ENZ. LGALS1 knockout caused G2/M phase arrest and inhibited cell motility and adhesion in PC3 cells, but had no effect on 22Rv1 cells. RNA-Seq results suggested that LGALS1 may be involved in the energy metabolism of cancer cells.

Conclusions:

ENZ is only effective in prostate cancer cells expressing AR. Inhibition of LGALS1 enhances ENZ sensitivity in AR-expressing cells by suppressing energy metabolism. LGALS1 inhibition also reduces cell growth, migration, and adhesion in cells with high LGALS1 expression. These findings may provide a theoretical basis for developing new treatment strategies for prostate cancer.