Kim Hogyoung, Abd Elmageed Zakaria Y, Davis Christian, El-Bahrawy Ali H, Naura Amarjit S, Ekaidi Ibrahim, Abdel-Mageed Asim B, Boulares A Hamid
The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, Southern University at New Orleans, New Orleans, Louisiana, United States of America.
Department of Urology, Tulane Medical Center, Southern University at New Orleans, New Orleans, Louisiana, United States of America.
Mol Med. 2014 Jul 14;20(1):270-9. doi: 10.2119/molmed.2013.00166.
PDZ domain containing 1 (PDZK1) is a scaffold protein that plays a role in the fate of several proteins. Estrogen can induce PDZK1 gene expression; however, our recent report showed that PDZK1 expression in the breast cancer cell line MCF-7 is indirect and involves insulin-like growth factor (IGF)-1 receptor function. Such a relationship was established in cell culture systems and human breast cancer tissues. Here we show that overexpression of PDZK1 promoted an increase in cyclin D1 and enhanced anchorage-independent growth of MCF-7 cells in the absence of 17β-estradiol, suggesting that PDZK1 harbors oncogenic activity. Indeed, PDKZ1 overexpression enhanced epidermal growth factor receptor (EGFR)-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation. PDZK1 appeared to play this role, in part, by stabilizing the integrity of the growth promoting factors Akt, human epidermal growth factor receptor 2 (Her2/Neu) and EGFR. Increased Akt levels occurred via a decrease in the ubiquitination of the kinase. PDZK1 overexpression was associated with resistance to paclitaxel/5-fluorouracil/etoposide only at low concentrations. Although the increased stability of Akt was sensitive to heat shock protein 90 (HSP90) inhibition, increased levels of the cochaperone cell division cycle 37 (Cdc37), as well as its ability to bind PDZK1, appear to play a larger role in kinase stability. Using human tissue microarrays, we show strong positive correlation between PDZK1, Akt and Cdc37 protein levels, and all correlated with human breast malignancy. There were no positive correlations between PDZK1 and Cdc37 at the mRNA levels, confirming our in vitro studies. These results demonstrate a relationship between PDZK1, Akt and Cdc37, and potentially Her2/Neu and EGFR, in breast cancer, representing a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.
含PDZ结构域1（PDZK1）是一种支架蛋白，在多种蛋白质的命运中发挥作用。雌激素可诱导PDZK1基因表达；然而，我们最近的报告显示，乳腺癌细胞系MCF-7中PDZK1的表达是间接的，且涉及胰岛素样生长因子（IGF）-1受体功能。这种关系在细胞培养系统和人乳腺癌组织中得以确立。在此我们表明，在不存在17β-雌二醇的情况下，PDZK1的过表达促进细胞周期蛋白D1增加，并增强MCF-7细胞的非锚定依赖性生长，提示PDZK1具有致癌活性。事实上，PDKZ1过表达增强了表皮生长因子受体（EGFR）刺激的MEK/ERK1/2信号传导以及IGF诱导的Akt磷酸化。PDZK1似乎部分通过稳定促进生长因子Akt、人表皮生长因子受体2（Her2/Neu）和EGFR的完整性来发挥这一作用。Akt水平的增加是通过激酶泛素化减少而发生的。仅在低浓度时，PDZK1过表达与对紫杉醇/5-氟尿嘧啶/依托泊苷的耐药性相关。尽管Akt稳定性的增加对热休克蛋白90（HSP90）抑制敏感，但伴侣蛋白细胞分裂周期37（Cdc37）水平的增加及其与PDZK1结合的能力似乎在激酶稳定性中发挥更大作用。使用人组织微阵列，我们显示PDZK1、Akt和Cdc37蛋白水平之间存在强正相关，且所有这些都与人类乳腺恶性肿瘤相关。在mRNA水平上，PDZK1与Cdc37之间无正相关，这证实了我们的体外研究。这些结果证明了乳腺癌中PDZK1、Akt和Cdc37之间的关系，以及潜在的Her2/Neu和EGFR之间的关系，代表了一个可用于治疗靶向以减轻人类乳腺癌负担的新轴。
