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Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling

Oncogene volume 24, pages 1338–1347 (2005)Cite this article

Abstract

Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling and oncogenesis. Utilizing MCF-7 human breast cancer cells, stably transfected with caveolin-1 (MCF-7/Cav1), we previously demonstrated that caveolin-1 expression decreases MCF-7 cell proliferation and colony formation in soft agar. However, the loss of anchorage-independent growth is associated with inhibition of anoikis, as MCF-7/Cav1 cells exhibit increased survival after detachment. Herein we show that this phenotype is associated with suppression of detachment-induced activation of p53 and of the consequent induction of cyclin-dependent kinase inhibitor p21WAF1/Cip1. In contrast, activation of p53 and p21WAF1/Cip1 induced by doxorubicin in MCF-7/Cav1 cells remains largely unaffected. The phenotypic changes observed in MCF-7/Cav1 cells are not accompanied by changes in caspase-6, -7, -8 and -9 and cannot be explained by changes in Bid and Bcl-2 expression. However, MCF-7/Cav1 cells exhibit a constitutively phosphorylated Akt kinase and at least one phosphorylated high molecular weight putative Akt substrate which we designated pp340. In addition, MCF-7/Cav1 cells exhibit elevated expression of insulin-like growth factor-I (IGF-I) receptor expression and increased IGF-I signaling to Erk1/2 and to Akt, as well as IGF-I-induced stimulation of pp340 phosphorylation. 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 in a time-dependent manner upon detachment of anoikis-resistant MCF-7/Cav1 cells and HT-29-MDR human multidrug resistant colon cancer cells. We conclude that expression of caveolin-1 in human breast cancer cells enhances matrix-independent cell survival that is mediated by upregulation of IGF-I receptor expression and signaling.

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Abbreviations

ECM:

extracellular matrix

IGF-I:

insulin-like growth factor-I

MTT:

3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

PI3K:

phosphoinositide 3-kinase

poly-HEMA:

poly-hydroxyethylmethacrylate

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Acknowledgements

We thank Yona Ely and Tovi Harel-Orbital for excellent technical assistance and all members of our groups for many helpful discussions. We are grateful to Drs Reuven Agami (NKI, Amsterdam), Moshe Oren and Atan Gross (WIS, Rehovot), Orna Halevy (HUJ, Rehovot), Anat Erdreich-Epstein (USC, Los Angeles) and Alex Toker (HMS, Boston) for reagents and counsel. This research was supported in part by a grant from the Ministry of Science and Technology (Jerusalem, Israel) and the Deutsches Krebsforschungszentrum (Heidelberg, Germany) (ML), and a grant from the Israel Cancer association (HW). DR is the recipient of the Rita Gehl Predoctoral Scholarship in Cancer Research. ML is the incumbent of the Harold L Korda Professorial Chair in Biology.

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Authors and Affiliations

  1. Department of Biological Regulation, Weizmann Institute of Science, Candiotty 138, PO Box 26, Rehovot, 76100, Israel

    Dana Ravid & Mordechai Liscovitch

  2. Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Sharon Maor & Haim Werner

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  1. Dana Ravid
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Correspondence to Mordechai Liscovitch.

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Ravid, D., Maor, S., Werner, H. et al. Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. Oncogene 24, 1338–1347 (2005). https://doi.org/10.1038/sj.onc.1208337

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