Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis
Ravshan Burikhanov,
Nikhil Hebbar,
Sunil K. Noothi,
Nidhi Shukla,
James Sledziona,
Nathália Araujo,
Meghana Kudrimoti,
Qing Jun Wang,
David S. Watt,
Danny R. Welch,
Jodi Maranchie,
Akihiro Harada,
Vivek M. Rangnekar
Affiliations
Ravshan Burikhanov
Department of Radiation Medicine, University of Kentucky, Lexington, KY 40356, USA
Nikhil Hebbar
Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA
Sunil K. Noothi
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY 40356, USA
Nidhi Shukla
Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA
James Sledziona
Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA
Nathália Araujo
Graduate Center for Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40356, USA
Meghana Kudrimoti
Department of Radiation Medicine, University of Kentucky, Lexington, KY 40356, USA
Qing Jun Wang
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
David S. Watt
Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40356, USA; Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40356, USA
Danny R. Welch
Department of Cancer Biology, University of Kansas, Kansas City, KS 66160, USA
Jodi Maranchie
Department of Urology, University of Pittsburgh, Pittsburgh, PA 15232, USA
Akihiro Harada
Department of Cell Biology, Osaka University, Osaka 565-0871, Japan
Vivek M. Rangnekar
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; Corresponding author
Summary: 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. : Burikhanov et al. identify the anti-malarial drug chloroquine (CQ) as a robust secretagogue of tumor suppressor Par-4. CQ-inducible Par-4 secretion is dependent on p53 and Rab8b for vesicle transport. Induction of Par-4 secretion provides an attractive option for the re-purposing of existing drugs for apoptosis and inhibition of tumor metastasis. Keywords: chloroquine, Par-4, p53, apoptosis, Rab8b, secretagogues, metastasis-inhibition
