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.
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This work was supported by NIH/NCI grants R01 CA165469, R01 CA187273, and R21 CA179283 (to V.M.R.). D.S.W. was supported by grant P30 RR020171 from the NIGMS to L. Hersh. N.A. was supported by a scholarship (ID 13137-13-1) from Coordenação de Aperfeiçoamento Superior (CAPES), Brazil. J.S. was supported by NCI grant T32 CA165990 (to V.M.R.).
Burikhanov, Ravshan; Hebbar, Nikhil; Noothi, Sunil K.; Shukla, Nidhi; Sledziona, James; Araujo, Nathália; Kudrimoti, Meghana; Wang, Qing Jun; Watt, David S.; Welch, Danny R.; Maranchie, Jodi; Harada, Akihiro; and Rangnekar, Vivek M., "Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis" (2017). Radiation Medicine Faculty Publications. 6.