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

Authors

Ravshan Burikhanov, University of KentuckyFollow
Nikhil Hebbar, University of KentuckyFollow
Sunil K. Noothi, University of Kentucky
Nidhi Shukla, University of KentuckyFollow
James Sledziona, University of KentuckyFollow
Nathália Araujo, University of KentuckyFollow
Meghana Kudrimoti, University of KentuckyFollow
Qing Jun Wang, University of KentuckyFollow
David S. Watt, University of KentuckyFollow
Danny R. Welch, University of Kansas
Jodi Maranchie, University of Pittsburgh
Akihiro Harada, Osaka University, Japan
Vivek M. Rangnekar, University of KentuckyFollow

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.

Document Type

Article

Publication Date

1-10-2017

Notes/Citation Information

Published in Cell Reports, v. 18, issue 2, p. 508-519.

© 2016 The Author(s).

Published under the Creative Commons Attribution 4.0 International license.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.celrep.2016.12.051

Funding Information

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.).

Repository Citation

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.
https://uknowledge.uky.edu/radmed_facpub/6