Extracellular Matrix Induced Drug Resistance and Tumor Survival in Prostate Cancer

Abstract

Castration-resistant prostate cancer (CRPC) often develops in patients that fail to respond to androgen deprivation therapy (ADT). Patients with CRPC have a low survival rate and understanding its mode of drug resistance is vital in the development of therapeutic agents to treat CRPC. CRPC also demonstrates resistance to specific inhibitors such as PI3K inhibitors. The extracellular matrix has been implicated in promoting drug resistance in various cancers. Prior studies indicate that adhesion to laminin promoted drug resistance in an androgen receptor (AR) dependent manner. However, due to the copious amount of collagen found throughout the body, especially in the bone where CRPC metastases are preferentially localized, I hypothesized that collagen induces drug resistance in prostate cancer. PC-3 Puro, PC-3 AR1, PC-3 AR2, and C4-2 cells adhered to laminin or collagen were treated with PI3K inhibitors (LY294002 or PX-866). Resistance to the drug was monitored via cell death assay that examined cell viability status by trypan blue exclusion. Prostate cancer cells adhered to collagen demonstrated resistance against LY294002 and PX-866 in an AR independent manner. Immunoblot analysis indicated a collagen induced upregulation of MRP1 and MCL-1, which was blocked by AR. Treatment with S63845, an MCL-1 inhibitor, re-sensitized the cells to PX-866 and LY294002. Collectively, these results indicate collagen induces drug resistance in prostate cancer cells in an AR independent manner. However, further analysis is required to determine the precise mechanism that upregulates MCL-1 and MRP1 in collagen-induced drug resistance.