P2X7 receptors and epithelial cancers

Abstract

AbstractThe P2X7A receptor is the main physiological pro‐apoptotic mechanism in epithelia in vivo. The natural ligand of the P2X7A is ATP. The P2X7A is expressed abundantly in epithelial reserve (stem) cells, and it regulates epithelial‐cell terminal differentiation. The high expression of P2X7A in reserve cells renders the cells sensitive to conditions of increased extracellular ATP, in particular upon neoplastic transformation, and to the induction of apoptosis. Cellular expression of the P2X7A is reduced in cancer cells of epithelia derived from the ectoderm, the urogenital sinus, and the distal paramesonephric duct. Low levels of P2X7A have been linked to cancer development because reserve cells harboring a defective P2X7A mechanism can escape P2X7A pro‐apoptotic control. Mechanisms that induce reduced expression of P2X7A in cancer epithelial cells involve hypermethylation of the P2X7 gene and decreased transcription; enhanced degradation of the P2X7 transcript through the action of micro‐RNAs miR‐186 and miR‐150; and epidermal growth factor (EGF) regulated, protein kinase‐A (PKA)‐mediated de‐glycosylation of the P2X7A. Reduced cellular P2X7A content has been proposed as a biomarker for human breast, bladder, ectocervix, endocervix, and endometrial cancers. The chemotherapeutic potential of augmented P2X7A‐dependent apoptosis of neoplastic epithelial cells was recently demonstrated in the mouse in vivo. Local treatment on the skin with the P2X7A‐specific agonist benzoyl‐ATP (BzATP) decreased the development of 7,12‐dimethyl‐benz(a)anthracene (DMBA)/12‐O‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced skin papillomas and skin cancers by 50%, by an effect that involves augmentation of keratinocytes reserve cells apoptosis. The P2X7A mechanism represents a novel pharmaceutical target for the prevention and treatment of epithelial neoplasia through the induction of apoptosis. WIREs Membr Transp Signal 2012,1:349–371. doi: 10.1002/wmts.33For further resources related to this article, please visit the WIREs website.