Targeting G-Protein Signaling for the Therapeutics of Prostate Tumor Bone Metastases and the Associated Chronic Bone Pain.

摘要

Bone tumor metastasis is the major cause of mortality and morbidity in advanced prostate cancer patients. These patients frequently suffer from moderate to severe chronic bone pain. However, the current treatments for these patients are ineffective and non-curative, because metastatic tumors are resistant to most of the current anti-cancer treatments, and the currently used pain therapeutic medications or analgesics often do not provide effective relief from pain due to the development of tolerance upon chronic use, and also have serious side effects. Thus, it is imperative to develop novel approaches that can both effectively block tumor growth in bones and relieve the associated bone cancer pain. This proposal aims to define the key role of the G beta gamma subunits of heterotrimeric G proteins in the development of prostate tumor bone metastasis and the associated bone pain. Our studies by far have demonstrated that G beta gamma signaling plays a key role in mediating proliferation of several prostate cancer cell lines, including LNCaP, PC3, DU145 and 22Rv1. Moreover, we show that activation of G protein-coupled receptor does not cause transactivation of androgen receptors. Rather, these receptors may stimulate prostate cancer cell growth and migration through several signaling pathways, including PI3K/AKT, ERK and calcium signaling that are activated downstream of G beta gamma.