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Phospholipase D confers rapamycin resistance in human breast cancer cells

Oncogene volume 22, pages 3937–3942 (2003)Cite this article

Abstract

mTOR (mammalian target of rapamycin) is a protein kinase that regulates cell cycle progression and cell growth. Rapamycin is a highly specific inhibitor of mTOR in clinical trials for the treatment of breast and other cancers. mTOR signaling was reported to require phosphatidic acid (PA), the metabolic product of phospholipase D (PLD). PLD, like mTOR, has been implicated in survival signaling and the regulation of cell cycle progression. PLD activity is frequently elevated in breast cancer. We have investigated the effect of rapamycin on breast cancer cell lines with different levels of PLD activity. MCF-7 cells, with relatively low levels of PLD activity, were highly sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells, with a 10-fold higher PLD activity than MCF-7 cells, were highly resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. These data implicate mTOR as a critical target for survival signals generated by PLD and suggest that PLD levels in breast cancer could be a valuable indicator of the likely efficacy of rapamycin treatment.

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Acknowledgements

We thank M Frohman (SUNY, Stony Brook) for the hPLD1 and mPLD2 genes used to generate the inducible PLD expression vectors. This investigation was supported by a grant from the National Cancer Institute CA46677, and from a SCORE grant from the National Institutes of Health GM60654. Research Centers in Minority Institutions award RR-03037 from the National Center for Research Resources of the National Institutes of Health, which supports infrastructure and instrumentation in the Biological Sciences Department at Hunter College, is also acknowledged.

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  1. Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Avenue, New York, 10021, NY, USA

    Yuhong Chen, Yang Zheng & David A Foster

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Correspondence to David A Foster.

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Chen, Y., Zheng, Y. & Foster, D. Phospholipase D confers rapamycin resistance in human breast cancer cells. Oncogene 22, 3937–3942 (2003). https://doi.org/10.1038/sj.onc.1206565

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