Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells.
Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells.
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DOI：
10.1158/0008-5472.can-09-1636
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Brown PH
中科院分区：
文献类型：
--
作者：
Chen L;Mayer JA;Krisko TI;Speers CW;Wang T;Hilsenbeck SG;Brown PH
p38激酶是丝裂原活化蛋白激酶（MAPK）家族的成员，可转导来自各种环境胁迫、生长因子和类固醇激素的信号。P38在侵袭性和侵袭性乳腺癌中高度表达。激活p38水平升高是不良预后的标志。在这项研究中，我们验证了阻断p38信号会抑制乳腺癌细胞增殖的假设。我们通过三种独立的方法研究了p38阻断后乳腺癌细胞增殖和细胞周期调节：显性阴性构建体、siRNA和小分子抑制剂。P38α和p38δ是所有乳腺肿瘤和乳腺癌细胞系中表达量最多的亚型。显性阴性p38的表达抑制了MDA-MB-468细胞的锚定依赖性和非依赖性增殖。siRNA沉默p38α抑制MDA-MB-468细胞的增殖，而不抑制p38δ。p38的药理抑制剂显著抑制p53突变体和er阴性乳腺癌细胞的增殖。虽然p38先前被认为是应激诱导细胞凋亡的中介，但我们提出p38可能具有调节生存和增殖的双重活性，这取决于p53的表达。我们的数据表明p38在表达突变型而非野生型p53的乳腺癌细胞中介导增殖信号。由于大多数er阴性乳腺癌肿瘤表达p53突变体，我们的研究结果为未来开发p38抑制剂以靶向p38治疗p53突变体和er阴性乳腺癌提供了基础。
p38 kinases are members of the mitogen-activated protein kinase (MAPK) family that transduce signals from various environmental stresses, growth factors and steroid hormones. p38 is highly expressed in aggressive and invasive breast cancers. Increased levels of activated p38 are markers of poor prognosis. In this study we tested the hypothesis that blockade of p38 signaling would inhibit breast cancer cell proliferation. We studied breast cancer cell proliferation and cell cycle regulation upon p38 blockade by using three independent approaches: dominant-negative constructs, siRNA, and small molecule inhibitors. p38α and p38δ are the most abundant isoforms expressed by all examined human breast tumors and breast cancer cell lines. Expression of a dominant-negative p38 inhibited both anchorage-dependent and -independent proliferation of MDA-MB-468 cells. Silencing of p38α, but not p38δ, using siRNA suppressed MDA-MB-468 cell proliferation. Pharmacological inhibitors of p38 significantly inhibited the proliferation of p53 mutant and ER-negative breast cancer cells. While p38 has previously been considered as a mediator of stress-induced apoptosis, we propose that p38 may have dual activities regulating survival and proliferation depending on the expression of p53. Our data suggest that p38 mediates the proliferation signal in breast cancer cells expressing mutant but not wild-type p53. Since most of ER-negative breast tumors express mutant p53, our results provide the foundation for future development of p38 inhibitors to target p38 for the treatment of p53 mutant and ER-negative breast cancers.