Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras.
Phospholipase D (PLD) is elevated in rodent fibroblasts expressing activated H-Ras mutants. We therefore examined the PLD activity in human cancer cells with activating Ras mutations. T24 bladder carcinoma cells express an activated H-Ras gene and Calu-1 lung carcinoma cells express an activated K-Ras gene. We report here that both of these cancer cell lines express highly elevated levels of PLD activity and that the PLD activity is dependent upon Ras. We also show that the PLD activity is dependent upon the Ras effector molecules RalA and phosphatidylinositol-3-kinase (PI3K). PLD activity has been shown to provide a survival signal in breast cancer cell lines that suppressed stress-induced apoptosis. Suppression of PLD activity in the T24 and Calu-1 cells resulted in apoptotic cell death in the absence of serum, indicating that the elevated PLD activity provided a survival signal in these cancer cell lines. Suppression of Ras, RalA, or PI3K also led to apoptosis in the absence of serum. These data indicate that a critical component of Ras signaling in human cancer cells is the activation of PLD and that targeting PLD survival signals in cancer cells could be an effective strategy to induce apoptosis in human cancers with activating Ras mutations.
Shi
Ming
M
Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Avenue, New York, NY 10021, USA .
Zheng
Yang
Y
Garcia
Avalon
A
Xu
Lizhong
L
Foster
David A
DA
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010739:Phospholipase D; D011065:Poly(ADP-ribose) Polymerases; D034741:RNA, Small Interfering; D020725:ral GTP-Binding Proteins; D018631:ras Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C492198:RALA protein, human