Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling
G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2020.608044/full |
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| author | Stefanie Chan Emma Smith Yuan Gao Julian Kwan Benjamin C. Blum Andrew M. Tilston-Lunel Isabella Turcinovic Xaralabos Varelas Maria Dafne Cardamone Stefano Monti Andrew Emili Andrew Emili Valentina Perissi |
| author_facet | Stefanie Chan Emma Smith Yuan Gao Julian Kwan Benjamin C. Blum Andrew M. Tilston-Lunel Isabella Turcinovic Xaralabos Varelas Maria Dafne Cardamone Stefano Monti Andrew Emili Andrew Emili Valentina Perissi |
| author_sort | Stefanie Chan |
| collection | DOAJ |
| description | G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs. |
| first_indexed | 2024-12-14T12:52:13Z |
| format | Article |
| id | doaj.art-36d3e03aaf634881b39db43ee4e2522c |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-14T12:52:13Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-36d3e03aaf634881b39db43ee4e2522c2022-12-21T23:00:39ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-01-01810.3389/fcell.2020.608044608044Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT SignalingStefanie Chan0Emma Smith1Yuan Gao2Julian Kwan3Benjamin C. Blum4Andrew M. Tilston-Lunel5Isabella Turcinovic6Xaralabos Varelas7Maria Dafne Cardamone8Stefano Monti9Andrew Emili10Andrew Emili11Valentina Perissi12Department of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesCenter for Network Systems Biology, Boston University, Boston, MA, United StatesCenter for Network Systems Biology, Boston University, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesCenter for Network Systems Biology, Boston University, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesDivision of Computational Biology, Department of Medicine, Boston University School of Medicine, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesCenter for Network Systems Biology, Boston University, Boston, MA, United StatesDepartment of Biochemistry, Boston University School of Medicine, Boston, MA, United StatesG Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.https://www.frontiersin.org/articles/10.3389/fcell.2020.608044/fullbreast cancerGPS2ubiquitin (Ub)MK2206 (PubChem CID: 46930998)Akt |
| spellingShingle | Stefanie Chan Emma Smith Yuan Gao Julian Kwan Benjamin C. Blum Andrew M. Tilston-Lunel Isabella Turcinovic Xaralabos Varelas Maria Dafne Cardamone Stefano Monti Andrew Emili Andrew Emili Valentina Perissi Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling Frontiers in Cell and Developmental Biology breast cancer GPS2 ubiquitin (Ub) MK2206 (PubChem CID: 46930998) Akt |
| title | Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling |
| title_full | Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling |
| title_fullStr | Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling |
| title_full_unstemmed | Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling |
| title_short | Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling |
| title_sort | loss of g protein pathway suppressor 2 promotes tumor growth through activation of akt signaling |
| topic | breast cancer GPS2 ubiquitin (Ub) MK2206 (PubChem CID: 46930998) Akt |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2020.608044/full |
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