Research Papers:

Tunicamycin induced endoplasmic reticulum stress promotes apoptosis of prostate cancer cells by activating mTORC1

Prasun Guha, Engin Kaptan, Padmaja Gade, Dhananjaya V. Kalvakolanu and Hafiz Ahmed _

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Oncotarget. 2017; 8:68191-68207. https://doi.org/10.18632/oncotarget.19277

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Prasun Guha1,4, Engin Kaptan1,5, Padmaja Gade2, Dhananjaya V. Kalvakolanu2,3 and Hafiz Ahmed1,3,6

1Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine and Institute of Marine and Environmental Technology, Baltimore, Maryland, USA

2Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA

3University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA

4Current address: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

5Current address: Department of Biology, Istanbul University, Vezneciler, Istanbul, Turkey

6Current address: GlycoMantra Inc., Baltimore, Maryland, USA

Correspondence to:

Hafiz Ahmed, email: [email protected]

Keywords: apoptosis, tunicamycin, ER stress, oxidative burst, metastatic cancer

Abbreviations: ER, endoplasmic reticulum; ROS, reactive oxygen species; Tun, tunicamycin; CQ, chloroquine; PBS, phosphate-buffered saline (10 mM phosphate, 140 mM NaCl, pH 7.5)

Received: May 04, 2017    Accepted: June 10, 2017    Published: July 15, 2017


Studies suggest that tunicamycin may work as a therapeutic drug to cancer cells by inducing stress in the endoplasmic reticulum (ER) through unfolded protein response (UPR) and thereby promoting apoptosis. However, mechanisms of the prolonged activation of the UPR under sustained ER stress in the regulation of cell apoptosis are largely unknown. To delineate the role of candidate genes in the apoptotic process under ER stress and to search for new therapeutic strategies to treat metastatic castration resistant prostate cancer, we performed whole genome expression microarray analysis in tunicamycin treated metastatic androgen-insensitive prostate cancer cells, PC-3. Among several induced genes, the expression of eNOS (NOS3) gene was remarkably high. The increased expression of eNOS activates mTORC1 through RagC. This results into an accumulation of p62 (SQSTM1) which facilitates aggregation of ubiquitinated protein thus compromising clearance of misfolded toxic protein aggregates. Lastly, association of p62 proteins and misfolded proteins promote reactive oxygen species (ROS) mediated mitochondrial apoptosis. Overall, our data demonstrate that tunicamycin induced ER stress promotes prostate cancer cell death by activating mTORC1 through eNOS-RagC pathway.

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