Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells
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 hete...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/6/1631 |
| _version_ | 1797564755164004352 |
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| author | Silvia Caggia Subhasish Tapadar Bocheng Wu Smrruthi V. Venugopal Autumn S. Garrett Aditi Kumar Janae S. Stiffend John S. Davis Adegboyega K. Oyelere Shafiq A. Khan |
| author_facet | Silvia Caggia Subhasish Tapadar Bocheng Wu Smrruthi V. Venugopal Autumn S. Garrett Aditi Kumar Janae S. Stiffend John S. Davis Adegboyega K. Oyelere Shafiq A. Khan |
| author_sort | Silvia Caggia |
| collection | DOAJ |
| description | 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 small molecule inhibitors that are able to prevent specifically the activation of the Gα<sub>i</sub>2 subunit, keeping the protein in its inactive GDP-bound state. We observed that two of the compounds (<b>13</b> and <b>14</b>) at 10 μΜ significantly inhibited the migratory behavior of the PC3 and DU145 prostate cancer cell lines. Additionally, compound <b>14</b> at 10 μΜ blocked the activation of Gα<sub>i</sub>2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of Gα<sub>i</sub>2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of Gα<sub>i</sub>2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of Gα<sub>i</sub>2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites. |
| first_indexed | 2024-03-10T19:01:24Z |
| format | Article |
| id | doaj.art-94f5655d531b4c709838fe83025e0e98 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:01:24Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-94f5655d531b4c709838fe83025e0e982023-11-20T04:24:29ZengMDPI AGCancers2072-66942020-06-01126163110.3390/cancers12061631Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer CellsSilvia Caggia0Subhasish Tapadar1Bocheng Wu2Smrruthi V. Venugopal3Autumn S. Garrett4Aditi Kumar5Janae S. Stiffend6John S. Davis7Adegboyega K. Oyelere8Shafiq A. Khan9Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USASchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30318, USASchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30318, USACenter for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USACenter for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USACenter for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USACenter for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USADepartment of Obstetrics and Gynecology, College of Medicine, University of Nebraska Medical Center and VA Medical Center, Omaha, NE 68198, USASchool of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30318, USACenter for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USAHeterotrimeric 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 small molecule inhibitors that are able to prevent specifically the activation of the Gα<sub>i</sub>2 subunit, keeping the protein in its inactive GDP-bound state. We observed that two of the compounds (<b>13</b> and <b>14</b>) at 10 μΜ significantly inhibited the migratory behavior of the PC3 and DU145 prostate cancer cell lines. Additionally, compound <b>14</b> at 10 μΜ blocked the activation of Gα<sub>i</sub>2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of Gα<sub>i</sub>2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of Gα<sub>i</sub>2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of Gα<sub>i</sub>2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites.https://www.mdpi.com/2072-6694/12/6/1631Gα<sub>i</sub>2cell migrationsmall molecule inhibitorscancerinvasion |
| spellingShingle | Silvia Caggia Subhasish Tapadar Bocheng Wu Smrruthi V. Venugopal Autumn S. Garrett Aditi Kumar Janae S. Stiffend John S. Davis Adegboyega K. Oyelere Shafiq A. Khan Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells Cancers Gα<sub>i</sub>2 cell migration small molecule inhibitors cancer invasion |
| title | Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells |
| title_full | Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells |
| title_fullStr | Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells |
| title_full_unstemmed | Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells |
| title_short | Small Molecule Inhibitors Targeting Gα<sub>i</sub>2 Protein Attenuate Migration of Cancer Cells |
| title_sort | small molecule inhibitors targeting gα sub i sub 2 protein attenuate migration of cancer cells |
| topic | Gα<sub>i</sub>2 cell migration small molecule inhibitors cancer invasion |
| url | https://www.mdpi.com/2072-6694/12/6/1631 |
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