N-(3-oxo-acyl) homoserine lactone inhibits tumor growth independent of Bcl-2 proteins
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Guoping Zhao1,6, Aaron M. Neely1, Christian Schwarzer3, Huayi Lu4, Aaron G. Whitt1, Nicole S. Stivers1, Joseph A. Burlison2, Carl White5, Terry E. Machen3, Chi Li1
1Molecular Targets Program, University of Louisville, Louisville, KY 40202, USA
2Structural Biology Program, James Graham Brown Cancer Center, Departments of Medicine, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
3Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
4Second Hospital of Jilin University, Changchun, Jilin Province, P.R. China 130041
5Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
6Institute of Technical Biology and Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui Province, P.R. China 230031
Chi Li, e-mail: [email protected]
Keywords: homoserine lactone, Bcl-2, Bak, Bax, tumor
Received: July 17, 2015 Accepted: December 22, 2015 Published: January 07, 2016
Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule for bacterial communication. C12 has also been reported to induce apoptosis in various types of tumor cells. However, the detailed molecular mechanism of C12-triggerred tumor cell apoptosis is still unclear. In addition, it is completely unknown whether C12 possesses any potential therapeutic effects in vivo. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in tumor cells through inducing mitochondrial membrane permeabilization independent of both pro- and anti-apoptotic Bcl-2 proteins. Importantly, C12 inhibits tumor growth in animals regardless of either pro- or anti-apoptotic Bcl-2 proteins. Furthermore, opposite to conventional chemotherapeutics, C12 requires paraoxonase 2 (PON2) to exert its cytotoxicity on tumor cells in vitro and its inhibitory effects on tumor growth in vivo. Overall, our results demonstrate that C12 inhibits tumor growth independent of both pro- and anti-apoptotic Bcl-2 proteins, and through inducing unique apoptotic signaling mediated by PON2 in tumor cells.
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