Elevated phospholipase D (PLD) activity has been reported in several types of human cancer including breast, kidney, colon and gastric cancer. Recent work has revealed that elevated PLD activity in human breast cancer cells can suppress apoptosis and promote cell migration - two critical steps in progression to a malignant cancer. The survival and migration signals generated by PLD are mediated - at least in part - by mTOR (the mammalian target of rapamycin), which has been widely implicated in cancer survival signals. While it is clear that PLD is capable of contributing to tumorigenesis and that PLD activity is elevated in a large number of human cancers, it is not known how and in what context elevated PLD activity contributes to the transformation of human cells or tumorigenesis in an animal. There is also much to be learned about the signaling pathways that activate PLD in human cancer cells. The Central Hypothesis of the proposal is that: PLD generates signals that suppress apoptosis and enhance cell migration in human cancer cells. Specifically, we propose to: 1) Characterize signals regulating PLD activity in human cancer cell lines and to evaluate targeting these signals pharmacologically both in vitro and in vivo; 2) Investigate a role for PLD survival signals in cell migration and metastasis; and 3) Evaluate the ability of PLD to cooperate with oncogenes to transform human cells in culture and to stimulate cell migration. The ability of PLD to both suppress apoptosis and enhance cell migration makes PLD an ideal target for the development of therapeutic strategies. As the era of molecular medicine and pathology evolves and individual tumors are examined at the molecular level, elevated PLD activity could be easily determined and the signals generated by PLD activity could then be targeted specifically. The studies proposed here will provide a conceptual framework for rational targeting of the apparent large number of human cancers with elevated PLD activity. ? ? ?
| Utter, Matthew; Chakraborty, Sohag; Goren, Limor et al. (2018) Elevated phospholipase D activity in androgen-insensitive prostate cancer cells promotes both survival and metastatic phenotypes. Cancer Lett 423:28-35 |
| Bernfeld, Elyssa; Menon, Deepak; Vaghela, Vishaldeep et al. (2018) Phospholipase D-dependent mTOR complex 1 (mTORC1) activation by glutamine. J Biol Chem 293:16390-16401 |
| Patel, Deven; Salloum, Darin; Saqcena, Mahesh et al. (2017) A Late G1 Lipid Checkpoint That Is Dysregulated in Clear Cell Renal Carcinoma Cells. J Biol Chem 292:936-944 |
| Menon, Deepak; Salloum, Darin; Bernfeld, Elyssa et al. (2017) Lipid sensing by mTOR complexes via de novo synthesis of phosphatidic acid. J Biol Chem 292:6303-6311 |
| Patel, Deven; Menon, Deepak; Bernfeld, Elyssa et al. (2016) Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells. J Biol Chem 291:9322-9 |
| Mukhopadhyay, Suman; Frias, Maria A; Chatterjee, Amrita et al. (2016) The Enigma of Rapamycin Dosage. Mol Cancer Ther 15:347-53 |
| Saqcena, Mahesh; Patel, Deven; Menon, Deepak et al. (2015) Apoptotic effects of high-dose rapamycin occur in S-phase of the cell cycle. Cell Cycle 14:2285-92 |
| Mukhopadhyay, Suman; Chatterjee, Amrita; Kogan, Diane et al. (2015) 5-Aminoimidazole-4-carboxamide-1-?-4-ribofuranoside (AICAR) enhances the efficacy of rapamycin in human cancer cells. Cell Cycle 14:3331-9 |
| LeGendre, Onica; Breslin, Paul As; Foster, David A (2015) (-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization. Mol Cell Oncol 2:e1006077 |
| Mukhopadhyay, Suman; Saqcena, Mahesh; Chatterjee, Amrita et al. (2015) Reciprocal regulation of AMP-activated protein kinase and phospholipase D. J Biol Chem 290:6986-93 |
Showing the most recent 10 out of 33 publications
