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

摘要

Bone metastasis is one of the most common and severe complications in advanced prostate cancer . It is the major cause of mortality and morbidities, due to the development of bone pain, hypercalcemia, fractures, spinal cord compression and consequent paralysis. The current regimen for these patients is largely palliative and non-curative, because metastatic tumors are resistant to most of the current anti-cancer treatments. Thus, it is imperative to develop novel therapeutic approaches for the treatment of advance prostate cancer. This proposal aims to define the key role of the G subunits of heterotrimeric G proteins in the development of prostate tumor bone metastasis and the associated bone pain, as well as determine the potential therapeutic efficacy of targeting G with small molecule inhibitors in preclinical models of bone-metastasized prostate cancer. G proteins mediate the function of a large group of cell surface receptor proteins called G protein-coupled receptors (GPCRs). Comparative experimental and clinical evidence has indicated that excessive activation of the GPCR systems due to overexpression of the receptors and their ligands in prostate tumor cells or their surrounding cells contributes to the metastatic spread of tumor cells to bones, their subsequent growth there and the consequent bone destruction. Moreover, continue activation of GPCRs in the sensory nerve fibers adjacent to bones results in increased activity/expression of key pain-sensing receptor channels, such as TRPV1, such that the channels are constitutively activated, leading to the sensation of chronic pain without any overt stimulation. Thus, the GPCR system represents an attractive target for the therapeutics of bone tumor metastasis and the associated bone pain.