Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide

被引:43
|
作者
Quann, Kevin [1 ]
Gonzales, Donna M. [1 ]
Mercier, Isabelle [1 ,2 ]
Wang, Chenguang [1 ]
Sotgia, Federica [1 ,2 ,3 ,4 ]
Pestell, Richard G. [5 ]
Lisanti, Michael P. [1 ,2 ,3 ,4 ]
Jasmin, Jean-Francois [1 ,2 ]
机构
[1] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Kimmel Canc Ctr, Jefferson Stem Cell Biol & Regenerat Med Ctr, Philadelphia, PA 19107 USA
[3] Univ Manchester, Manchester Breast Ctr, Manchester, Lancs, England
[4] Univ Manchester, Breakthrough Breast Canc Res Unit, Paterson Inst Canc Res, Inst Canc Sci,Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England
[5] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
关键词
Caveolin-1; glioma; brain cancer; tumor progression; tumor suppressor; microarray; mouse model; chemotherapy; temozolomide; BLOOD-BRAIN-BARRIER; P42/44 MAP KINASE; IN-VIVO; MOLECULAR PATHOLOGY; MALIGNANT GLIOMAS; GENE-EXPRESSION; CELL-LINES; CANCER; FIBROBLASTS; ACTIVATION;
D O I
10.4161/cc.24497
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:1510 / 1520
页数:11
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