Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis

Abstract

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