Cancer-secreted AGR2 induces programmed cell death in normal cells.

Autor:	Vitello EA; Department of Urology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA., Quek SI; Department of Urology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.; Present address: Singapore Polytechnic, Center for Biomedical and Life Sciences, Singapore., Kincaid H; EDRN Informatics Center and NASA Jet Propulsion Laboratory, Pasadena, CA, USA., Fuchs T; EDRN Informatics Center and NASA Jet Propulsion Laboratory, Pasadena, CA, USA., Crichton DJ; EDRN Informatics Center and NASA Jet Propulsion Laboratory, Pasadena, CA, USA., Troisch P; Insititute for Systems Biology, Seattle, WA, USA., Liu AY; Department of Urology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 Aug 02; Vol. 7 (31), pp. 49425-49434.
DOI:	10.18632/oncotarget.9921
Abstrakt:	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. Competing Interests: The authors do not have any conflicts of interest.
Databáze:	MEDLINE
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