PPP1CA and RPSA dual inhibition suppresses castration resistance and bone metastasis for prostate cancer by disrupting AR-V7/RANKL signaling

Androgen is important in the formation, development and progress of prostate cancer, and deprivation of androgen, which is also named castration, is an effective way in prostate cancer therapies. For patients undergoing castration therapies, castration was gradually becoming ineffective in prostate cancer treatment and therefore resulting in castration-resistance for prostate cancer. Co-IP mass spectrometry, Ribo-seq, RNA-seq and system biology methods were applied to detect castration resistance drivers. Ribosomal drivers were found to be highly expressed and promoting invasion and migration in castration resistant prostate cancer cells and also in bone metastasis prostate cancer cells. Within these ribosomal drivers, RPSA played central roles in promoting castration resistance in assistance of RPL28, RPL4X, RPL11 and RPL23A. RPSA promotes castration resistance through interacting with PPP1CA and AR-V7 to form RPSA-PPP1CA-AR-V7 axis. This axis is bind by RPL23A and RPL28 and assisted by RPL4X. IGF-1 is also engaged in the process of promoting castration resistance and bone metastasis by RPSA-PPP1CA-AR-V7 axis. RPSA inhibitors plus PPP1CA inhibitors have also been proven to significantly restore castration resistance and bone metastasis for prostate cancer. This effect can be reversed by IGF-1 and retinoid acid. For these reasons, we propose that dual inhibition of RPSA and PPP1CA significantly inhibits castration resistance and bone metastasis for prostate cancer.