Membrane translocation and activation of GnRH receptor sensitize prostate cancer cells to radiation. (2nd November 2021)

• Record Type: Journal Article
• Authors: Sánchez, Catherine; Mercado, Alejandro; Contreras, Héctor R.; Carvajal V, Felipe; Salgado, Apolo; Huidobro, Christian; Castellón, Enrique A.
• Is Part Of: International journal of radiation biology. Volume 97:Number 11(2021)
• Page Start: 1555
• Page End: 1562
• Publication Date: 2021-11-02
• Subjects: Prostate cancer -- primary cell cultures -- leuprolide and GnRH analogs -- GnRH receptor (GnRHR) -- radiotherapy -- pharmacoperone IN3; Radiation -- Physiological effect -- Periodicals; Radiobiology -- Periodicals; 571.45
• DOI: 10.1080/09553002.2021.1980628
• Languages: English
• ISSNs: 0955-3002

Abstract

Abstract: Background: GnRH analogs are widely used as neoadjuvant agents for radiotherapy in prostate cancer (PCa) patients, with well-documented effects in reducing tumor bulk and increasing progression-free survival. GnRH analogs act locally in the prostate by triggering apoptosis of PCa cells via activation of the GnRH receptor (GnRHR). During PCa progression, the distribution of GnRHR within the cell is altered, with reduced expression in the cell membrane and remaining sequestered in the endoplasmic reticulum. Pharmacoperone IN3 is able to relocalize GnRHR to the cell membrane. The aim of this study was to evaluate the effect of radiation on PCa cells pretreated with leuprolide, alone or in combination with IN3, as radiosensitizers. Material and methods: PC3 and human PCa primary cell cultures were treated with IN3 for 24 h, followed by different doses of leuprolide for 48 h and, finally, single doses of radiation (3, 6, and 9 Gy). After radiation, cell survival, apoptosis, cell cycle distribution, and colony growth were evaluated. Results: Radiation reduced cell survival and increased apoptosis in a dose-dependent manner. This effect was also directly related to leuprolide concentration. Pretreatment with IN3 enhanced apoptosis and decreased cell survival, also observing a higher proportion of cells arrested in G2. Conclusion: Neoadjuvant leuprolide increases radiation-mediated apoptosis of PCa cells. This effect was enhanced by pretreatment with pharmacoperone IN3. Clinical use of IN3 as a radiosensitizer combined with androgen deprivation therapy to improve survival of patients with PCa remains to be evaluated.