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.

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…3,4 Temozolomide (TMZ), as currently the most promising chemotherapeutic drug, is applied to treat malignant glioma, including GBM. 5,6 However, TMZ is not always effective in patients with GBM, and the intrinsic or acquired chemoresistance of GBM cells always results in this unsatisfactory outcome. 7 A large number of epidemiological studies on cancer incidence link the propensity of cancers with the individual's obesity.…”

Caveolin-1 Expression is Associated with Tumor Size and Therapy Response in Wilms Tumor

“…Previous studies showed that Cav1 facilitate both ERK and AKT signaling in cancer cells from kidney, ovary, colon, prostate, epidermis, muscle, brain and is associated with promoting cell invasion, proliferation, angiogenesis and multi-drug resistance. [12][13][14][15][16][17][18][19][20] Most authors suggested that Cav-1 positive tumor cells served as tumor promoters by these signaling pathways. 3,[12][13][14][15][16][17][18][19] In the present study, we determined Cav-1 expression nearly in the half of tumors.…”

“…Recent studies have also focused their attention on Cav-1 expression in the peritumoral stromal cells rather than Cav-1 expression in the tumor cells. [12][13][14][15][16][17] For example Goetz et al suggest that there may be an important role for stromal Cav-1 in promoting tumor progression and metastasis. 20 But in the most other studies, loss of stromal Cav-1 expression in association with the high tumoral Cav-1 expression, has been reported to be closely related with poor outcome in different malignancies.…”

Microarray Analysis in Glioblastomas

“…Only high-quality RNA, having a RIN of >7.0 and an A260/280 absorbance ratio of >1.8, should be utilized for further experimentation. This step is particularly important for RNA derived from paraffin-embedded tissue, whose purity may be limited, often requiring re-purification (11). …”