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.

Primary Cilia as Signaling Hubs in Health and Disease

“…[160] The mutations in ciliary genes cause the loss of primary cilia on SHH medulloblastoma cells and confer resistance to SMO inhibitors due to the lack of GLI-R and the presence of full-length GLI2, the latter of which can work as a weak transcriptional activator without SMO signaling. [172,173] Hedgehog signaling in cancer can be regulated by the UPS. [160,163,164] Several strategies can be considered to overcome this drug resistance, including the inhibition of GLI-A and reintroduction of primary cilia.…”

“…Several strategies can be considered to overcome this drug resistance, including the inhibition of GLI‐A and reintroduction of primary cilia . Small molecules have been identified that inhibit GLI‐A and reintroduce primary cilia …”

Novel functions of the primary cilium in bone disease and cancer

“…Using a highcontent analysis-based approach, Khan, Garg, Agostinis, and Swinnen (2018) proved that restoration of the primary cilium in cancer cells was a promising novel approach to attenuate tumor growth. Using a highcontent analysis-based approach, Khan, Garg, Agostinis, and Swinnen (2018) proved that restoration of the primary cilium in cancer cells was a promising novel approach to attenuate tumor growth.…”

“…Furthermore, the length and formation of primary cilia in cancer tissues can be changed after antineoplastic treatment. Using a highcontent analysis-based approach, Khan, Garg, Agostinis, and Swinnen (2018) proved that restoration of the primary cilium in cancer cells was a promising novel approach to attenuate tumor growth. This group screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells.…”

“…Most compounds attenuated cell proliferation, at least in part through the induction of primary cilium formation, as demonstrated by cilium removal using 4 mM chloral hydrate (≥98%), which abolishes the primary cilium by disrupting the junction between the cilium and the basal body and is currently one of the only chemical methods for removing primary cilia from vertebrate cells (Khan et al, 2018).…”