Cancer-secreted AGR2 induces programmed cell death in normal cells
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Elizabeth A. Vitello1, Sue-Ing Quek1,4, Heather Kincaid2, Thomas Fuchs2, Daniel J. Crichton2, Pamela Troisch3, Alvin Y. Liu1
1Department of Urology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
2EDRN Informatics Center and NASA Jet Propulsion Laboratory, Pasadena, CA, USA
3Insititute for Systems Biology, Seattle, WA, USA
4Present address: Singapore Polytechnic, Center for Biomedical and Life Sciences, Singapore
Elizabeth A. Vitello, email: [email protected]
Keywords: AGR2, prostate cancer cell types, prostate stromal cells, programmed cell death, SAT1
Received: February 17, 2016 Accepted: May 23, 2016 Published: June 08, 2016
Anterior Gradient 2 (AGR2) is a protein expressed in many solid tumor types including prostate, pancreatic, breast and lung. AGR2 functions as a protein disulfide isomerase in the endoplasmic reticulum. However, AGR2 is secreted by cancer cells that overexpress this molecule. Secretion of AGR2 was also found in salamander limb regeneration. Due to its ubiquity, tumor secretion of AGR2 must serve an important role in cancer, yet its molecular function is largely unknown. This study examined the effect of cancer-secreted AGR2 on normal cells. Prostate stromal cells were cultured, and tissue digestion media containing AGR2 prepared from prostate primary cancer 10-076 CP and adenocarcinoma LuCaP 70CR xenograft were added. The control were tissue digestion media containing no AGR2 prepared from benign prostate 10-076 NP and small cell carcinoma LuCaP 145.1 xenograft. In the presence of tumor-secreted AGR2, the stromal cells were found to undergo programmed cell death (PCD) characterized by formation of cellular blebs, cell shrinkage, and DNA fragmentation as seen when the stromal cells were UV irradiated or treated by a pro-apoptotic drug. PCD could be prevented with the addition of the monoclonal AGR2-neutralizing antibody P3A5. DNA microarray analysis of LuCaP 70CR media-treated vs. LuCaP 145.1 media-treated cells showed downregulation of the gene SAT1 as a major change in cells exposed to AGR2. RT-PCR analysis confirmed the array result. SAT1 encodes spermidine/spermine N1-acetyltransferase, which maintains intracellular polyamine levels. Abnormal polyamine metabolism as a result of altered SAT1 activity has an adverse effect on cells through the induction of PCD.
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