Abstract
Heterotrimeric G-proteins are ubiquitously expressed in several cancers, and they transduce signals from activated G-protein coupled receptors. These proteins have numerous biological functions, and they are becoming interesting target molecules in cancer therapy. Previously, we have shown that heterotrimeric G-protein subunit alphai2 (Gαi2) has an essential role in the migration and invasion of prostate cancer cells. Using a structure-based approach, we have synthesized optimized small molecule inhibitors that are able to prevent specifically the activation of the Gαi2 subunit, keeping the protein in its inactive GDP-bound state. We observed that two of the compounds (13 and 14) at 10 μΜ significantly inhibited the migratory behavior of the PC3 and DU145 prostate cancer cell lines. Additionally, compound 14 at 10 μΜ blocked the activation of Gαi2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of Gαi2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of Gαi2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of Gαi2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites.
Highlights
IntroductionMetastatic transformation is a complex process, driven by a cascade of biological events—collectively defined as the metastatic cascade—which starts from the escape of the epithelial cells from the primary tumors, invasion throughout the surrounding extracellular matrix (ECM) and stromal cell layers, intravasation into the blood vessels, survival in the circulation, arrival to distant organ sites, extravasation into the parenchyma of the distant organs, the initial formation of micrometastasis, and starting of the proliferation at the metastatic sites, with a subsequent generation of neoplastic growths, known as “metastatic colonization” [1,2]
Metastasis is the leading cause of mortality of patients with cancer
We have shown that Gαi 2 acts at two distinct levels, to induce cell migration in prostate cancer cells
Summary
Metastatic transformation is a complex process, driven by a cascade of biological events—collectively defined as the metastatic cascade—which starts from the escape of the epithelial cells from the primary tumors, invasion throughout the surrounding extracellular matrix (ECM) and stromal cell layers, intravasation into the blood vessels, survival in the circulation, arrival to distant organ sites, extravasation into the parenchyma of the distant organs, the initial formation of micrometastasis, and starting of the proliferation at the metastatic sites, with a subsequent generation of neoplastic growths, known as “metastatic colonization” [1,2]. From which cancer cells develop, are very tightly close to each other, through a very complex architecture of proteins and junctions, such as adherens junctions, desmosomes and tight junctions [3]. Some of the players which have crucial roles during this metastatic transformation are the integrins, which have important functions during the intra- and extravasation processes [4]
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