title: Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis.
abstract: The induction of tumor suppressor proteins capable of cancer cell apoptosis represents an attractive option for the re-purposing of existing drugs. We report that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial. CQ-inducible Par-4 secretion triggers paracrine apoptosis of cancer cells and also inhibits metastatic tumor growth. CQ induces Par-4 secretion via the classical secretory pathway that requires the activation of p53. Mechanistically, p53 directly induces Rab8b, a GTPase essential for vesicle transport of Par-4 to the plasma membrane prior to secretion. Our findings indicate that CQ induces p53- and Rab8b-dependent Par-4 secretion from normal cells for Par-4-dependent inhibition of metastatic tumor growth.
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.affiliation: Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hebbar
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Noothi
authors.affiliation: Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Shukla
authors.affiliation: Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: James
authors.initials: J
authors.lastname: Sledziona
authors.affiliation: Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Nathália
authors.initials: N
authors.lastname: Araujo
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Kudrimoti
authors.affiliation: Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA; Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: Qing Jun
authors.initials: QJ
authors.lastname: Wang
authors.affiliation: Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40356, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40356, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
authors.affiliation: Department of Cancer Biology, University of Kansas, Kansas City, KS 66160, USA.
authors.forename: Danny R
authors.initials: DR
authors.lastname: Welch
authors.affiliation: Department of Urology, University of Pittsburgh, Pittsburgh, PA 15232, USA.
authors.forename: Jodi
authors.initials: J
authors.lastname: Maranchie
authors.affiliation: Department of Cell Biology, Osaka University, Osaka 565-0871, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Harada
authors.affiliation: Department of Radiation Medicine, University of Kentucky, Lexington, KY 40356, USA; Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA; Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40356, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40356, USA. Electronic address: vmrang01@email.uky.edu.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Rangnekar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015513:Oncogene Proteins / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D018179:Receptors, Thrombin / Q000378:metabolism*; D055571:Secretory Pathway / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020691:rab GTP-Binding Proteins
chemical_list: D015513:Oncogene Proteins; C529761:Rab8b protein, human; D018179:Receptors, Thrombin; D016159:Tumor Suppressor Protein p53; D002738:Chloroquine; D020691:rab GTP-Binding Proteins; C112908:protease-activated receptor 4
keywords: Par-4; Rab8b; apoptosis; chloroquine; metastasis-inhibition; p53; secretagogues