Identification of drugs that restore primary cilium expression in cancer cells

Abstract

The development of cancer is often accompanied by a loss of the primary cilium, a microtubule-based cellular protrusion that functions as a cellular antenna and that puts a break on cell proliferation. Hence, restoration of the primary cilium in cancer cells may represent a novel promising approach to attenuate tumor growth. Using a high content analysis-based approach we screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells. A diverse set of 118 compounds stimulating cilium expression was identified. These included glucocorticoids, fibrates and other nuclear receptor modulators, neurotransmitter regulators, ion channel modulators, tyrosine kinase inhibitors, DNA gyrase/topoisomerase inhibitors, antibacterial compounds, protein inhibitors, microtubule modulators, and COX inhibitors. Certain compounds also dramatically affected the length of the cilium. For a selection of compounds (Clofibrate, Gefitinib, Sirolimus, Imexon and Dexamethasone) their ability to restore ciliogenesis was confirmed in a panel of human cancer cell line models representing different cancer types (pancreas, lung, kidney, breast). Most compounds attenuated cell proliferation, at least in part through induction of the primary cilium, as demonstrated by cilium removal using chloral hydrate. These findings reveal that several commonly used drugs restore ciliogenesis in cancer cells, and warrant further investigation of their antineoplastic properties.

Mixed signals from the cell's antennae: primary cilia in cancer

“…Elevated transcript levels of SPEN were found to be indicative of a better prognosis in triple-negative breast cancer. The hormone-independent function of SPEN complements to the original finding that SPEN acts as a tumor suppressor in breast cancer by acting as a transcriptional co-repressor of estrogen receptor alpha [95,96].…”

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.…”

Depletion of primary cilium in acral melanoma

“…Primary cilia loss, therefore, represents a potential cellular similarity between acral melanoma and other types of CMM as well as other types of malignancy that has downstream signaling consequences, rendering cilia a unique target of therapeutic intervention . Whether cilia loss occurs in acral melanoma, however, has not been reported and addressing this possibility was the primary aim of our pilot study.…”