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

doi:10.1016/j.celrep.2016.12.051

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

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56 Scopus citations

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.

Original language	English
Pages (from-to)	508-519
Number of pages	12
Journal	Cell Reports
Volume	18
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2016.12.051
State	Published - Jan 10 2017

Bibliographical note

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.). We thank Jason Brandon, PhD, for participating in the mouse experiments.

Publisher Copyright:
© 2017 The Author(s)

Keywords

Par-4
Rab8b
apoptosis
chloroquine
metastasis-inhibition
p53
secretagogues

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.12.051

Cite this

Burikhanov, R., Hebbar, N., Noothi, S. K., Shukla, N., Sledziona, J., Araujo, N., Kudrimoti, M., Wang, Q. J., Watt, D. S., Welch, D. R., Maranchie, J., Harada, A., & Rangnekar, V. M. (2017). Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis. Cell Reports, 18(2), 508-519. https://doi.org/10.1016/j.celrep.2016.12.051

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

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.",

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author = "Ravshan Burikhanov and Nikhil Hebbar and Noothi, {Sunil K.} and Nidhi Shukla and James Sledziona and Nath{\'a}lia Araujo and Meghana Kudrimoti and Wang, {Qing Jun} and Watt, {David S.} and Welch, {Danny R.} and Jodi Maranchie and Akihiro Harada and Rangnekar, {Vivek M.}",

note = "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 Coordena{\c c}{\~a}o de Aperfei{\c c}oamento Superior (CAPES), Brazil. J.S. was supported by NCI grant T32 CA165990 (to V.M.R.). We thank Jason Brandon, PhD, for participating in the mouse experiments. Publisher Copyright: {\textcopyright} 2017 The Author(s)",

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AU - Burikhanov, Ravshan

AU - Hebbar, Nikhil

AU - Noothi, Sunil K.

AU - Shukla, Nidhi

AU - Sledziona, James

AU - Araujo, Nathália

AU - Kudrimoti, Meghana

AU - Wang, Qing Jun

AU - Watt, David S.

AU - Welch, Danny R.

AU - Maranchie, Jodi

AU - Harada, Akihiro

AU - Rangnekar, Vivek M.

N1 - 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.). We thank Jason Brandon, PhD, for participating in the mouse experiments. Publisher Copyright: © 2017 The Author(s)

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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