Stress and cancer progression: novel roles for the α 1 ‐adrenergic receptor and PLD1

We've identified the presence of α 1 ‐adrenergic receptors (AR) in Chinese Hamster Lung Cells (CCL39). Stimulation with phenylephrine (PE) activates Phospholipase D (PLD) and increases ERK phosphorylation. PE stimulation also activates the Na + ‐ H + exchanger (NHE), induces stress fiber formation, and activates Matrixmetalloproteinase 9 (MMP9). Inhibition of ERK using blocks NHE and MMP9 activation as well as stress fiber formation. PE activation of ERK is also blocked in the presence of primary butanol demonstrating that PLD is upstream of ERK. PE activation of PLD is blocked by d/n PLD1 but not by d/n PLD2 providing evidence that PLD1 is the only PLD isoform involved in PE signaling. PE induced increases of ERK phosphorylation was also blocked by dominant negative RAS indicating that PLD activates the RAS/ERK pathway through phosphatidic acid (PA) and the activation of RAS. Addition of short chain PA leads to activation of RAS and ERK. Cell migration and invasion was measured and in both cases, cell motility was decreased by inhibiting ERK, NHE or PLD. We conclude that AR signals through PLD1 and ERK. Secondly, PE stimulates cell migration and invasion in a manner that requires PLD, ERK, and NHE. These results indicate a role for elevated stress hormone levels increasing cancer progression. We are investigating the role of this signaling process in human lung cancer cells. NSF‐MCB‐0080243; NIH 1 R15 HL074924‐01A1