title: TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma.
abstract: Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1).
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Hall
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA; Division of Pediatric Urology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Cost
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Hegde
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Kellner
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Mikhaylova
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Stratton
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ehmer
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Abplanalp
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: Raghav
authors.initials: R
authors.lastname: Pandey
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biesiada
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Harteneck
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Plas
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Informatics, Nicolas Copernicus University, 87-100 Torun, Poland.
authors.forename: Jarek
authors.initials: J
authors.lastname: Meller
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA; Department of Veterans Affairs, VA Research Service, Cincinnati, OH 45220, USA. Electronic address: maria.czyzykkrzeska@uc.edu.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Czyzyk-Krzeska
mesh_terms: D000818:Animals; D001343:Autophagy; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology*; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D009368:Neoplasm Transplantation; D009857:Oncogenes; D034622:RNA Interference; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D050053:TRPM Cation Channels; C475667:TRPM3 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human