Cancer-secreted AGR2 induces programmed cell death in normal cells.
Cancer-secreted AGR2 induces programmed cell death in normal cells.
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DOI：
10.18632/oncotarget.9921
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发表时间：
2016-08-02
期刊：
影响因子：
--
通讯作者：
Liu AY
中科院分区：
文献类型：
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作者：
Vitello EA;Quek SI;Kincaid H;Fuchs T;Crichton DJ;Troisch P;Liu AY
前梯度2 （AGR2）是一种在多种实体肿瘤中表达的蛋白，包括前列腺、胰腺、乳腺和肺。AGR2在内质网中起蛋白二硫异构酶的作用。然而，AGR2是由过度表达该分子的癌细胞分泌的。在蝾螈肢体再生过程中也发现了AGR2的分泌。由于AGR2的普遍存在，肿瘤分泌一定在癌症中起重要作用，但其分子功能在很大程度上是未知的。这项研究检测了癌症分泌的AGR2对正常细胞的影响。培养前列腺基质细胞，加入由前列腺原发癌10-076 CP和腺癌LuCaP 70CR异种移植物制备的含有AGR2的组织消化培养基。对照为良性前列腺10-076 NP和小细胞癌lucap145.1异种移植制备的不含AGR2的组织消化培养基。在肿瘤分泌的AGR2存在的情况下，发现基质细胞发生程序性细胞死亡（PCD），其特征是细胞泡形成、细胞收缩和DNA断裂，如在基质细胞紫外线照射或用促凋亡药物处理时所见。添加单克隆ag2中和抗体P3A5可以预防PCD。对LuCaP 70CR培养基处理的细胞与LuCaP 145.1培养基处理的细胞的DNA微阵列分析显示，暴露于AGR2的细胞中，SAT1基因下调是主要变化。RT-PCR分析证实了阵列结果。SAT1编码亚精胺/精胺n1 -乙酰转移酶，维持细胞内多胺水平。由于SAT1活性改变导致的多胺代谢异常通过诱导PCD对细胞产生不利影响。
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.