The Chemosensory Function of Primary Cilia Regulates Cholangiocyte Migration, Invasion, and Tumor Growth.
AMP-Activated Protein Kinase Kinases
Adenosine Triphosphate
/ metabolism
Adenylyl Cyclases
/ metabolism
Animals
Bile Duct Neoplasms
/ etiology
Cell Line, Tumor
Cell Movement
Chemoreceptor Cells
/ physiology
Cholangiocarcinoma
/ etiology
Cilia
/ physiology
Cyclic AMP-Dependent Protein Kinases
/ metabolism
Humans
PTEN Phosphohydrolase
/ metabolism
Protein Serine-Threonine Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Rats
Receptors, Purinergic P2
/ metabolism
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
18
05
2018
accepted:
01
10
2018
pubmed:
10
10
2018
medline:
30
5
2020
entrez:
10
10
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30299561
doi: 10.1002/hep.30308
pmc: PMC6438749
mid: NIHMS992433
doi:
Substances chimiques
P2RY11 protein, human
0
Receptors, Purinergic P2
0
Adenosine Triphosphate
8L70Q75FXE
Protein Serine-Threonine Kinases
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
STK11 protein, human
EC 2.7.11.1
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
PTEN Phosphohydrolase
EC 3.1.3.67
Adenylyl Cyclases
EC 4.6.1.1
adenylyl cyclase type V
EC 4.6.1.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1582-1598Subventions
Organisme : NCI NIH HHS
ID : R01 CA183764
Pays : United States
Organisme : Hormel Foundation
Pays : International
Organisme : Randy Shaver Cancer Research and Community Fund
Pays : International
Informations de copyright
© 2018 by the American Association for the Study of Liver Diseases.
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