Drug-induced ciliogenesis in pancreatic cancer cells is facilitated by the secreted ATP-purinergic receptor signaling pathway

Abstract

Malignant transformation of cells is often accompanied by the loss of the primary cilium, a protruding microtubule-based sensory organelle, suggesting that it plays an “onco-suppressive” role. Therefore, restoration of the primary cilium is being explored as a new therapeutic approach to attenuate tumor growth. Recently, several commonly used chemotherapeutic drugs have been identified to induce the primary cilium in pancreatic cancer cells. The mechanisms by which these drugs re-express the cilium remain, however, enigmatic. Here, evaluation of a panel of diverse ciliogenic drugs on pancreatic cancer cell models revealed a significant positive relationship between drug-induced extracellular ATP, released through pannexin channels, and the extent of primary cilium induction. Moreover, cilium induction by these drugs was hampered in the presence of the ATP degrading enzyme, apyrase, and in the presence of the pan-purinergic receptor inhibitor, suramin. Our findings reveal that ciliogenic drug-induced re-expression of the primary cilium in pancreatic cancer cells is, at least in certain contexts, dependent on a hitherto unrecognized autocrine/paracrine loop involving the extracellular ATP-purinergic receptor signaling pathway that can be exploited in a therapeutic approach targeting at restoring the primary cilium.