Increased expression of the dsRNA-activated protein kinase PKR in breast cancer promotes sensitivity to doxorubicin.
Increased expression of the dsRNA-activated protein kinase PKR in breast cancer promotes sensitivity to doxorubicin.
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DOI：
10.1371/journal.pone.0046040
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
May WS Jr
中科院分区：
文献类型：
--
作者：
Bennett RL;Carruthers AL;Hui T;Kerney KR;Liu X;May WS Jr
据报道，干扰素诱导的dsRNA依赖性蛋白激酶PKR的表达和活性在乳腺癌细胞系和原发性肿瘤样品中增加。为了扩展这些发现并确定PKR信号传导如何影响乳腺癌细胞对化疗的敏感性，我们通过免疫组化染色检测了538例原发性乳腺癌和正常组织中PKR的表达。值得注意的是，与正常组织相比，PKR表达在导管癌、小叶癌和鳞状细胞癌或淋巴结转移中升高，但在良性肿瘤标本或炎症病例中不升高。此外，PKR的表达增加，在癌前阶段的乳腺细胞增生和异型增生的正常组织相比，表明PKR的表达可能是上调的过程中的肿瘤发生。为了测试PKR在乳腺癌中的功能，我们通过siRNA敲低产生了PKR表达显著降低的MCF 7、T-47 D和MDA-MB-231乳腺癌细胞系。重要的是，虽然PKR表达的敲低对正常生长条件下的细胞增殖没有影响，但与对照细胞相比，PKR表达降低或用小分子PKR抑制剂处理的MCF 7、T-47 D或MDA-MB-231细胞对阿霉素或H2 O2诱导的毒性的敏感性显著降低。此外，在PKR表达降低的乳腺癌细胞系中，阿霉素处理后eIF 2 α磷酸化速率延迟。值得注意的是，用干扰素-α（增加PKR表达）或salubrinal（增加eIF 2 α磷酸化）治疗PKR表达降低的乳腺癌细胞系，可使阿霉素敏感性恢复至正常水平。综上所述，这些结果表明，原发性乳腺癌组织中PKR表达增加可能作为含阿霉素化疗反应的生物标志物，未来促进PKR表达/活化和eIF 2 α磷酸化的治疗方法可能有利于乳腺癌的治疗。
It has been reported that the expression and activity of the interferon-inducible, dsRNA-dependent protein kinase, PKR, is increased in mammary carcinoma cell lines and primary tumor samples. To extend these findings and determine how PKR signaling may affect breast cancer cell sensitivity to chemotherapy, we measured PKR expression by immunohistochemical staining of 538 cases of primary breast cancer and normal tissues. Significantly, PKR expression was elevated in ductal, lobular and squamous cell carcinomas or lymph node metastases but not in either benign tumor specimens or cases of inflammation compared to normal tissues. Furthermore, PKR expression was increased in precancerous stages of mammary cell hyperplasia and dysplasia compared to normal tissues, indicating that PKR expression may be upregulated by the process of tumorigenesis. To test the function of PKR in breast cancer, we generated MCF7, T-47D and MDA-MB-231 breast cancer cell lines with significantly reduced PKR expression by siRNA knockdown. Importantly, while knockdown of PKR expression had no effect on cell proliferation under normal growth conditions, MCF7, T-47D or MDA-MB-231 cells with reduced PKR expression or treated with a small molecule PKR inhibitor were significantly less sensitive to doxorubicin or H2O2-induced toxicity compared to control cells. In addition, the rate of eIF2α phosphorylation following treatment with doxorubicin was delayed in breast cancer cell lines with decreased PKR expression. Significantly, treatment of breast cancer lines with reduced PKR expression with either interferon-α, which increases PKR expression, or salubrinal, which increases eIF2α phosphorylation, restored doxorubicin sensitivity to normal levels. Taken together these results indicate that increased PKR expression in primary breast cancer tissues may serve as a biomarker for response to doxorubicin-containing chemotherapy and that future therapeutic approaches to promote PKR expression/activation and eIF2α phosphorylation may be beneficial for the treatment of breast cancer.
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影响因子：
20.3
作者：
Bennett, Richard L.;Blalock, William L.;May, W. Stratford
通讯作者：
May, W. Stratford
影响因子：
11.5
作者：
Pataer, Abujiang;Raso, Maria Gabriela;Swisher, Stephen G.
通讯作者：
Swisher, Stephen G.
影响因子：
11.4
作者：
Kumar, A;Yang, YL;Williams, BRG
通讯作者：
Williams, BRG
影响因子：
8
作者：
Cuddihy, AR;Wong, AHT;Koromilas, AE
通讯作者：
Koromilas, AE
DOI：
10.1073/pnas.90.1.232
发表时间：
1993-01-01
影响因子：
11.1
作者：
MEURS, EF;GALABRU, J;HOVANESSIAN, AG
通讯作者：
HOVANESSIAN, AG