title: Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide.
abstract: Caveolin-1 (Cav-1) is a critical regulator of tumor progression in a variety of cancers where it has been shown to act as either a tumor suppressor or tumor promoter. In glioblastoma multiforme, it has been previously demonstrated to function as a putative tumor suppressor. Our studies here, using the human glioblastoma-derived cell line U-87MG, further support the role of Cav-1 as a negative regulator of tumor growth. Using a lentiviral transduction approach, we were able to stably overexpress Cav-1 in U-87MG cells. Gene expression microarray analyses demonstrated significant enrichment in gene signatures corresponding to downregulation of MAPK, PI3K/AKT and mTOR signaling, as well as activation of apoptotic pathways in Cav-1-overexpressing U-87MG cells. These same gene signatures were later confirmed at the protein level in vitro. To explore the ability of Cav-1 to regulate tumor growth in vivo, we further show that Cav-1-overexpressing U-87MG cells display reduced tumorigenicity in an ectopic xenograft mouse model, with marked hypoactivation of MAPK and PI3K/mTOR pathways. Finally, we demonstrate that Cav-1 overexpression confers sensitivity to the most commonly used chemotherapy for glioblastoma, temozolomide. In conclusion, Cav-1 negatively regulates key cell growth and survival pathways and may be an effective biomarker for predicting response to chemotherapy in glioblastoma.
authors.affiliation: Department of Stem Cell Biology & Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Quann
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gonzales
authors.forename: Isabelle
authors.initials: I
authors.lastname: Mercier
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jasmin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077204:Temozolomide; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D051242:Caveolin 1; D003606:Dacarbazine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide
keywords: Caveolin-1; brain cancer; chemotherapy; glioma; microarray; mouse model; temozolomide; tumor progression; tumor suppressor