The Chemosensory Function of Primary Cilia Regulates Cholangiocyte Migration, Invasion, and Tumor Growth

Adrian P. Mansini, Estanislao Peixoto, Sujeong Jin, Seth Richard, Sergio Gradilone

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Cholangiocytes, the epithelial cells lining the biliary tree in the liver, express primary cilia that can detect several kinds of environmental signals and then transmit this information into the cell. We have reported that cilia are significantly reduced in cholangiocarcinoma (CCA) and that the experimental deciliation of normal cells induces a malignant-like phenotype with increased proliferation, anchorage-independent growth, invasion, and migration. Here, we tested the hypothesis that the chemosensory function of cholangiocyte primary cilia acts as a mechanism for tumor suppression. We found that in the presence of extracellular nucleotides cilia-dependent chemosensation of the nucleotides inhibited migration and invasion in normal ciliated cholangiocytes through a P2Y11 receptor and liver kinase B1 (LKB1)–phosphatase and tensin homolog–AKT–dependent mechanism. In contrast, in normal deciliated cholangiocytes and CCA cells, the nucleotides induced the opposite effects, i.e., increased migration and invasion. As activation of LKB1 through a cilia-dependent mechanism was required for the nucleotide-mediated inhibitory effects on migration and invasion, we attempted to activate LKB1 directly, independent of ciliary expression, using the compound hesperidin methyl chalcone (HMC). We found that HMC induced activation of LKB1 in both ciliated and deciliated cells in vitro, resulting in the inhibition of migration and proliferation. Furthermore, using a rat syngeneic orthotopic CCA model, we found that HMC inhibited tumor growth in vivo. Conclusion: These findings highlight the importance of the chemosensory function of primary cilia for the control of migration and invasion and suggest that, by directly activating LKB1 and bypassing the need for primary cilia, it is possible to emulate this chemosensory function in CCA cells; these data warrant further studies evaluating the possibility of using HMC as therapy for CCA.

Original languageEnglish (US)
Pages (from-to)1582-1598
Number of pages17
Issue number4
StatePublished - Apr 2019

Bibliographical note

Funding Information:
Received May 18, 2018; accepted October 1, 2018. Additional Supporting Information may be found at Supported by the National Institutes of Health (R01CA183764, to S.A.G.), The Randy Shaver Cancer Research and Community Fund Award (to S.A.G.), and The Hormel Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. © 2018 by the American Association for the Study of Liver Diseases. View this article online at DOI 10.1002/hep.30308

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