Most prostate carcinomas require androgen stimulation to grow, and for nearly 70 years androgen ablation therapy has been one of the central therapeutic strategies against advanced prostate cancer. Although most tumours initially respond to this therapy, some will be acquired resistant and progress to metastatic castration-resistant (mCRPC) disease which clinically tends to progress more rapidly than earlier disease manifestations. The underlying molecular biology of mCRPC is highly complex, and numerous mechanisms have been proposed that promote and retain androgen independence. In various clinical and preclinical data explored, the nature of intracellular signalling pathways mediating mitogenic acquired resistant effects of GPCRs in prostate cancer is poorly defined. G-protein-coupled receptor kinase 2 (GRK2) contributes to the modulation of basic cellular functions-such as cell proliferation, survival, or motility-and is involved in metabolic homeostasis, inflammation, or angiogenic processes. Moreover, altered GRK2 levels are starting to be reported in different tumoural contexts and shown to promote breast tumourigenesis or to trigger the tumoural angiogenic switch. Thus, we are exploring recent findings that present unexpected opportunities to interfere with major tumourigenic signals by manipulating GPCR-mediated pathways.
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