title: A role for cAMP-driven transactivation of EGFR in cancer aggressiveness - therapeutic implications.
abstract: In many common cancers, production of cAMP boosts cancer proliferation, survival, and aggressiveness, reflecting the fact that, through mechanisms that require further clarification, cAMP can promote tyrosine phosphorylation, notably transactivation of the epidermal growth factor receptor (EGFR). Hormones which activate adenylate cyclase in many cancers include PGE2 - often produced by cox-2 activity within tumors - and adrenergic hormones, acting on beta2 receptors. NSAID cyclooxygenase inhibitors, including low-dose aspirin, clearly reduce risk for many adenocarcinomas, but the impact of cox-2 inhibitors in clinical cancer therapy remains somewhat equivocal. There is increasing evidence that increased sympathetic drive, often reflecting psychic stress or tobacco usage, increases risk for, and promotes the aggressiveness of, many cancers. The non-specific beta antagonist propranolol shows cancer-retardant activity in pre-clinical rodent studies, especially in stressed animals, and a limited amount of epidemiology concludes that concurrent propranolol usage is associated with superior prognosis in breast cancer, ovarian cancer, and melanoma. Epidemiology correlating increased resting heart rate with increased total cancer mortality can be interpreted as compelling evidence that increased sympathetic drive encourages the onset and progression of common cancers. Conversely, hormones which inhibit adenylate cyclase activity in cancers may have potential for cancer control; GABA, which can be administered as a well-tolerated nutraceutical, has potential in this regard. Combination regimens intended to down-regulate cancer cAMP levels, perhaps used in conjunction with EGFR inhibitors, may have considerable potential for suppressing the contribution of cAMP/EGFR to cancer aggressiveness. This model also predicts that certain other hormones which activate adenylate cylase in various tissue may play a yet-unsuspected role in cancer induction and spread.
authors.affiliation: Catalytic Longevity, 7831 Rush Rose Drive, Apt. 316, Carlsbad, CA 92009, United States. Electronic address: markfmccarty@gmail.com.
authors.forename: Mark F
authors.initials: MF
authors.lastname: McCarty
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D000262:Adenylyl Cyclases