Dataset Information

Small Molecule Inhibitors Targeting G?i2 Protein Attenuate Migration of Cancer Cells.

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 (G?i2) 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 G?i2 subunit, keeping the protein in its inactive GDP-bound state. We observed that two of the compounds (13 and 14) at 10 ?? significantly inhibited the migratory behavior of the PC3 and DU145 prostate cancer cell lines. Additionally, compound 14 at 10 ?? blocked the activation of G?i2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of G?i2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of G?i2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of G?i2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites.

SUBMITTER: Caggia S

PROVIDER: S-EPMC7353059 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells.

Caggia Silvia S Tapadar Subhasish S Wu Bocheng B Venugopal Smrruthi V SV Garrett Autumn S AS Kumar Aditi A Stiffend Janae S JS Davis John S JS Oyelere Adegboyega K AK Khan Shafiq A SA

Cancers 20200619 6

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 (Gα<sub>i</sub>2) has an essential role in the migration and invasion of prostate cancer cells. Using a structure-based approach, we have synthesized optimized sma ...[more]

PMID: 32575572

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Project description:The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases-USP14, RPN11, and UCH37-are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome's conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.

Dataset Information

Small Molecule Inhibitors Targeting G?i2 Protein Attenuate Migration of Cancer Cells.

Publications

Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells.

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