Andrew Feranchak, MD, Chief of Pediatric Gastroenterology and Associate director of PLRC, along with PLRC leaders Aatur Singhi, MD, Silvia Liu, PhD and Paul Monga, MD, published an article in American Journal of Physiology: Gastrointestinal Liver Physiology entitled, “TMEM16A partners with mTOR to influence pathways of cell survival, proliferation and migration in cholangiocarcinoma“.
Abstract
Expression of TMEM16A, a calcium activated chloride channel, is elevated in some human cancers and impacts tumor cell proliferation, metastasis and patient outcome. Evidence presented here uncovers a molecular synergy between TMEM16A and mTOR, a serine-threonine kinase that is known to promote cell survival and proliferation in cholangiocarcinoma (CCA), a lethal cancer of the secretory cells of bile ducts. Analysis of gene and protein expression in human CCA tissue and CCA cell line, detected elevated TMEM16A expression and Cl– channel activity. TMEM16A’s Cl– channel activity impacted the actin cytoskeleton and the ability of cells to survive, proliferate and migrate as revealed by pharmacological inhibition studies. The basal activity of mTOR too was elevated in the CCA cell line compared to the normal cholangiocytes. Molecular inhibition studies provided further evidence that TMEM16A and mTOR each was able to influence the regulation of the other’s activity or expression respectively. Consistent with this reciprocal regulation, combined TMEM16A and mTOR inhibition produced a greater loss of CCA cell survival and migration than their individual inhibition alone. Together these data reveal that the aberrant TMEM16A expression and cooperation with mTOR contributes to a certain advantage in CCA.
