PKCζ Promotes Breast Cancer Invasion by Regulating Expression of E-cadherin and Zonula Occludens-1 (ZO-1) via NFκB-p65.
PKCζ Promotes Breast Cancer Invasion by Regulating Expression of E-cadherin and Zonula Occludens-1 (ZO-1) via NFκB-p65.
复制标题
DOI：
10.1038/srep12520
复制
发表时间：
2015-07-28
影响因子：
4.6
通讯作者：
Paul S
中科院分区：
文献类型：
--
作者：
Paul A;Danley M;Saha B;Tawfik O;Paul S
非典型蛋白激酶Cζ (PKCζ)形成分裂缺陷（PAR）极性复合物，用于维持正常细胞连接复合物和组织稳态所必需的膜蛋白的顶-底分布。一致地，PKCζ的肿瘤抑制作用已在多种人类癌症中确立。然而，最近的研究也表明PKCζ的促癌功能没有明确的详细分子机制。在这里，我们报告了乳腺癌背景下致癌PKCζ信号传导的可能机制。我们观察到PKCζ的缺失促进了间充质样MDA-MB-231细胞的上皮形态。上皮形态的诱导与粘附连接（AJ）蛋白E-cadherin和紧密连接（TJ）蛋白zoonula Occludens-1 （ZO-1）的显著上调有关。功能上，PKCζ的缺失显著抑制侵袭和转移进展。一致地，我们观察到PKCζ信号在侵袭性和转移性乳腺癌中的表达和激活高于非侵袭性疾病。从机制上讲，致癌的PKCζ- NFκB-p65信号节点可能参与抑制E-cadherin和ZO-1的表达，而构成活性形式的NFκB-p65 （S536E-NFκB-p65）的异位表达显著地挽救了PKCζ-缺失的乳腺癌细胞的侵袭潜力。因此，我们的研究发现PKCζ - NFκB-p65信号通路可能参与改变乳腺癌侵袭性进展的细胞连接动力学。
Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for apico-basal distribution of membrane proteins essential to maintain normal cellular junctional complexes and tissue homeostasis. Consistently, tumor suppressive role of PKCζ has been established for multiple human cancers. However, recent studies also indicate pro-oncogenic function of PKCζ without firm understanding of detailed molecular mechanism. Here we report a possible mechanism of oncogenic PKCζ signaling in the context of breast cancer. We observed that depletion of PKCζ promotes epithelial morphology in mesenchymal-like MDA-MB-231 cells. The induction of epithelial morphology is associated with significant upregulation of adherens junction (AJ) protein E-cadherin and tight junction (TJ) protein Zonula Occludens-1 (ZO-1). Functionally, depletion of PKCζ significantly inhibits invasion and metastatic progression. Consistently, we observed higher expression and activation of PKCζ signaling in invasive and metastatic breast cancers compared to non-invasive diseases. Mechanistically, an oncogenic PKCζ– NFκB-p65 signaling node might be involved to suppress E-cadherin and ZO-1 expression and ectopic expression of a constitutively active form of NFκB-p65 (S536E-NFκB-p65) significantly rescues invasive potential of PKCζ-depleted breast cancer cells. Thus, our study discovered a PKCζ - NFκB-p65 signaling pathway might be involved to alter cellular junctional dynamics for breast cancer invasive progression.