Li Hua, Sun Grace Y, Zhao Yongchao, Thomas Dafydd, Greenson Joel K, Zalupski Mark M, Ben-Josef Edgar, Sun Yi
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
Oncotarget. 2014 Dec 30;5(24):12811-9. doi: 10.18632/oncotarget.2659.
DEPTOR was reported as a naturally occurring inhibitor of mTORC1 and mTORC2. The role of DEPTOR in the growth and survival of pancreatic cancer cells has not previously been determined. Here we report that while DEPTOR shows a cytoplasmic expression in both normal pancreatic acinar and islet cells in a patchy manner, its expression is reduced in PanIN1 and PanIN2 and completely lost in 100 out of 101 pancreatic ductal adenocarcinoma (PDAC) tissues. Ectopic DEPTOR expression in two pancreatic cancer cell lines, Panc-1 and Miapaca-2, caused a significant 1) suppression of anchorage-dependent growth in monolayer culture, particularly under conditions with growth factor deprivation; 2) decreased clonogenic survival, and 3) suppressed anchorage-independent growth in soft agar. These effects are attributable to moderate induction of apoptosis and growth arrest at the S and G2/M phases, in a cell line dependent manner. Furthermore, ectopic DEPTOR expression moderately inhibited mTORC1 activity, as demonstrated by reduced phosphorylation of S6K, S6, and 4E-BP1. Taken together, these data suggest that DEPTOR has a tumor suppressive activity against pancreatic cancer cells, and its loss of expression may contribute to pancreatic tumorigenesis.
DEPTOR被报道为mTORC1和mTORC2的天然抑制剂。此前尚未确定DEPTOR在胰腺癌细胞生长和存活中的作用。在此我们报告，虽然DEPTOR在正常胰腺腺泡细胞和胰岛细胞中呈散在的细胞质表达，但其在PanIN1和PanIN2中的表达降低，并且在101例胰腺导管腺癌（PDAC）组织中的100例中完全缺失。在两种胰腺癌细胞系Panc-1和Miapaca-2中异位表达DEPTOR，导致：1）在单层培养中显著抑制锚定依赖性生长，尤其是在生长因子剥夺的条件下；2）克隆形成存活率降低；3）在软琼脂中抑制锚定非依赖性生长。这些效应归因于细胞系依赖性的适度凋亡诱导以及在S期和G2/M期的生长停滞。此外，异位表达DEPTOR适度抑制mTORC1活性，这通过S6K、S6和4E-BP1磷酸化减少得以证明。综上所述，这些数据表明DEPTOR对胰腺癌细胞具有肿瘤抑制活性，其表达缺失可能有助于胰腺肿瘤发生。
