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

Cell Rep. 2017 Jan 10;18(2):508-519. doi: 10.1016/j.celrep.2016.12.051.

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.

Keywords: Par-4; Rab8b; apoptosis; chloroquine; metastasis-inhibition; p53; secretagogues.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chloroquine / pharmacology*
  • Humans
  • Mice
  • Neoplasm Metastasis
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Oncogene Proteins / metabolism
  • Paracrine Communication / drug effects
  • Receptors, Thrombin / metabolism*
  • Secretory Pathway / drug effects
  • Tumor Suppressor Protein p53 / metabolism
  • rab GTP-Binding Proteins

Substances

  • Oncogene Proteins
  • Rab8b protein, human
  • Receptors, Thrombin
  • Tumor Suppressor Protein p53
  • Chloroquine
  • rab GTP-Binding Proteins
  • protease-activated receptor 4