CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells.
CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells.
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DOI：
10.1158/0008-5472.can-10-2736
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Govindarajan R
中科院分区：
文献类型：
--
作者：
Bhutia YD;Hung SW;Patel B;Lovin D;Govindarajan R
克服胰腺癌固有的耐药性仍然是这种疾病治疗研究的主要目标。在这项研究中，我们发现了人浓缩核苷转运蛋白-1（hCNT 1; SLC 28 A1），一种高亲和力嘧啶核苷转运蛋白，在确定人胰腺癌细胞对吉西他滨（目前用作标准治疗药物）的化疗敏感性方面的作用。与正常胰腺和胰腺导管上皮细胞相比，hCNT 1在胰腺肿瘤和肿瘤细胞系中的表达经常降低。此外，hCNT 1介导的3 H-吉西他滨转运在胰腺癌细胞系中较低，并与吉西他滨的细胞毒性IC 50估计值相关。与吉西他滨敏感的胰腺癌细胞系相反，吉西他滨耐药的胰腺癌细胞系MIA PaCa-2表现出相对限制性的细胞周期依赖性hCNT 1表达和转运。hCNT 1翻译在晚期G1富集的MIA PaCa-2细胞群中可能以miRNA依赖性方式受到抑制，这与该阶段期间最低的hCNT 1介导的吉西他滨转运相对应。虽然hCNT 1蛋白在G1/S转换期间被诱导，但增加的hCNT 1运输导致G2/M期富集的细胞群体中的最大细胞表面募集和运输超调。hCNT 1蛋白在S或G2/M期MIA PaCa-2细胞中分别主要针对蛋白酶体或溶酶体降解。hCNT 1降解的药理学抑制适度增加了MIA PaCa-2细胞中细胞表面hCNT 1表达和细胞吉西他滨转运。组成性hCNT 1表达降低了MIA PaCa-2细胞的克隆存活率，并急剧增强了吉西他滨的转运和化疗增敏作用。除了支持hCNT 1的假定肿瘤抑制作用外，我们的研究结果还将hCNT 1确定为使耐药胰腺癌细胞适合化疗的潜在候选者。
Overcoming the inherent chemoresistance of pancreatic cancers remains a major goal of therapeutic investigations in this disease. In this study, we discovered a role for the human concentrative nucleoside transporter-1 (hCNT1; SLC28A1), a high-affinity pyrimidine nucleoside transporter, in determining the chemosensitivity of human pancreatic cancer cells to gemcitabine, the drug used presently as a standard of care. Compared with normal pancreas and pancreatic ductal epithelial cells, hCNT1 expression was frequently reduced in pancreatic tumors and tumor cell lines. In addition, hCNT1-mediated 3H-gemcitabine transport was lower in pancreatic cancer cell lines and correlated with cytotoxic IC50 estimations of gemcitabine. In contrast to gemcitabine-sensitive pancreatic cancer cell lines, MIA PaCa-2, a gemcitabine-resistant pancreatic cancer cell line exhibited relatively restrictive, cell cycle-dependent hCNT1 expression and transport. hCNT1 translation was suppressed in the late G1-enriched MIA PaCa-2 cell population possibly in an miRNA-dependent manner, which corresponded with the lowest hCNT1-mediated gemcitabine transport during this phase. While hCNT1 protein was induced during G1/S transition, increased hCNT1 trafficking resulted in maximal cell surface recruitment and transport-overshoot in the G2/M phase-enriched cell population. hCNT1 protein was directed predominantly to proteasomal or lysosomal degradation in S or G2/M phase MIA PaCa-2 cells, respectively. Pharmacological inhibition of hCNT1 degradation moderately increased cell surface hCNT1 expression and cellular gemcitabine transport in MIA PaCa-2 cells. Constitutive hCNT1 expression reduced clonogenic survival of MIA PaCa-2 cells and steeply augmented gemcitabine transport and chemosensitization. In addition to supporting a putative tumor suppressor role for hCNT1, our findings identify hCNT1 as a potential candidate to render drug-resistant pancreatic cancer cells amenable to chemotherapy.