Τρίτη 17 Απριλίου 2018

Targeting Galectin-1 impairs castration-resistant prostate cancer progression and invasion

Purpose: The majority of prostate cancer (PCa) patients 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 PCa progression and poor clinical outcome. The role of Gal-1 in tumor progression are largely unknown. Here we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1inhibitor, 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 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 anti-tumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of PCa cells in vivo. Conclusions: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.



https://ift.tt/2vnqvIL

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου