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Phospholipase D confers rapamycin resistance in human breast cancer cells
Yuhong Chen1, Yang Zheng, David A Foster
1Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Avenue, New York, NY 10021, USA.
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.
Insights
Phospholipase D (PLD) activity influences breast cancer cell response to rapamycin, an mTOR inhibitor. High PLD levels confer resistance, while low levels increase sensitivity, suggesting PLD as a predictive biomarker for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation, targeted by rapamycin for cancer therapy.
- Phosphatidic acid (PA), produced by phospholipase D (PLD), is essential for mTOR signaling.
- Elevated PLD activity is common in breast cancer and linked to survival signaling.
Purpose of the Study:
- To investigate the impact of varying phospholipase D (PLD) activity levels on breast cancer cell sensitivity to rapamycin.
- To determine if PLD levels can predict the efficacy of mTOR-targeted therapy in breast cancer.
Main Methods:
- Utilized breast cancer cell lines (MCF-7 and MDA-MB-231) with distinct endogenous PLD activity levels.
- Manipulated PLD activity in MCF-7 cells by elevation and in MDA-MB-231 cells by inhibition.
- Assessed cell sensitivity to rapamycin, including effects on growth arrest, S6 kinase phosphorylation, and Myc expression.
Main Results:
- MCF-7 cells (low PLD) showed high sensitivity to rapamycin, while MDA-MB-231 cells (high PLD) exhibited significant resistance.
- Increasing PLD activity in MCF-7 cells induced rapamycin resistance.
- Inhibiting PLD activity in MDA-MB-231 cells enhanced rapamycin sensitivity.
- Elevated PLD activity also conferred resistance to rapamycin's effects on S6 kinase phosphorylation and Myc expression.
Conclusions:
- Mammalian target of rapamycin (mTOR) signaling is critically dependent on survival signals generated by phospholipase D (PLD).
- Phospholipase D (PLD) activity levels in breast cancer correlate with the therapeutic efficacy of rapamycin.
- PLD levels represent a potential predictive biomarker for guiding rapamycin treatment decisions in breast cancer patients.