Caveolin-1 inhibits anoikis and promotes survival signaling in cancer cells

Dana Ravid, Sharon Maor, Haim Werner, Mordechai Liscovitch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Caveolin-1 is an essential protein constituent of plasma membrane caveolae and a regulator of caveolae-dependent signaling and endocytosis. In addition, caveolin-1 interacts with and modulates multiple signaling pathways, suggesting that its expression is likely to profoundly affect cell function and cell fate. Indeed, the expression of caveolin-1 is up regulated in terminally differentiated epithelial cells and, conversely, down regulated upon oncogenic transformation. Heterologous expression of caveolin-1 inhibits mitogenic signaling and abrogates anchorage-independent growth of cancer cells, while antisense suppression of caveolin-1 expression leads to fibroblast transformation. Finally, caveolin-1-null mice exhibit tissue-specific hyperplasia and increased sensitivity to oncogene- and carcinogen-induced tumorigenesis. Together with the chromosomal localization of caveolin-1 gene near a fragile site that is often deleted in human cancers (7q31.1/D7S522), these results led to the suggestion that caveolin-1 is a growth-inhibitory protein that may act as a tumor-suppressor. However, this idea is inconsistent with the fact that caveolin-1 is highly expressed in many cancer cell lines. This was originally demonstrated in human multidrug resistant cancer cells and in mouse metastatic prostate cancer cells. The data that have accumulated since reveal that there are major, divergent changes in caveolin-1 expression in human cancer cells and tumor specimens. In some forms of cancer caveolin-1 expression is down regulated, but in many other cancers caveolin-1 levels are high. The expression of caveolin-1 is positively correlated with the tumor cell grade and its progression stage and, in some cases, the expression of caveolin-1 was shown to be an independent predictor of poor disease prognosis. Why is a putative tumor suppressor protein like caveolin-1 highly expressed in so many cancer cells? Overexpression and gene-specific suppression studies leave little doubt that caveolin-1 has anti-proliferative actions in normal cells. This implies that caveolin-1 must have another function in advanced stage/high grade, metastatic and multidrug resistant cancer cells, in which its expression is maintained or is up regulated. One possibility is that in such cancer cells caveolin-1 promotes cell survival. It may be hypothesized that, at early stages of cancer progression (when rapid proliferation is essential for clonal expansion) expression of caveolin-1 is down regulated to suppress its growth inhibitory actions. Conversely, at late, advanced stages of the disease (when survival and stress resistance are paramount), expression of caveolin-1 is up regulated. Our current research aims to elucidate the function (s) of caveolin-1 in human cancer cell lines and to examine the hypothesis that its expression in advanced stage, multidrug resistant and/or metastatic cancer is related to its pro-survival actions. We have shown recently that stable expression of caveolin-1 in MCF-7 cells results in inhibition of anoikis, indicating that caveolin-1 promotes matrix-independent survival. Caveolin-1 expression also prevents detachment-induced activation of p53 and the consequent induction of p21Waf1/Cip1. MCF-7/Cav1 cells exhibit a constitutively phosphorylated Akt kinase, elevated IGF-I receptor expression and increased IGF-I signaling to Erk1/2 and to Akt. The addition of IGF-I to the medium rescues the parental MCF-7 cells from anoikis, indicating that IGF-1 can act as a survival factor for suspended MCF-7 cells. Finally, the levels of caveolin-1 are dramatically elevated upon detachment of anoikis-resistant MCF-7/Cav1 cells and HT-29-MDR human multidrug resistant colon cancer cells. In conclusion, expression of caveolin-1 in human breast cancer cells enhances matrix-independent cell survival by a mechanism that could be mediated by up-regulation of IGF-I receptor expression and signaling.

Original languageEnglish
Pages (from-to)163-175
Number of pages13
JournalAdvances in Enzyme Regulation
Issue number1
StatePublished - 2006


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