Role of the PI3K/Akt pathway in cadmium induced malignant transformation of normal prostate epithelial cells.
Role of the PI3K/Akt pathway in cadmium induced malignant transformation of normal prostate epithelial cells.
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DOI：
10.1016/j.taap.2020.115308
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发表时间：
2020-12-15
影响因子：
3.8
通讯作者：
Majid S
中科院分区：
文献类型：
--
作者：
Kulkarni P;Dasgupta P;Bhat NS;Hashimoto Y;Saini S;Shahryari V;Yamamura S;Shiina M;Tanaka Y;Dahiya R;Majid S
本研究探讨了PI 3 K/Akt通路在镉（Cd）诱导的正常前列腺上皮细胞（PWR 1 E和RWPE 1）恶性转化中的作用。将PWR 1 E和RWPE 1细胞暴露于10μM Cd中一年，并命名为Cd-PWR 1 E和Cd-RWPE 1。Cd-RWPE 1细胞在无胸腺裸鼠中稳健地形成肿瘤。在功能上，镉暴露诱导的致瘤属性表明增加伤口愈合，迁移和侵袭能力在两个细胞系。RT 2-array分析显示Cd-RWPE 1中的P110α、Akt、mTOR、NFKB 1和RAF等多种癌基因被诱导表达，而肿瘤抑制基因（TS）被减弱。这通过转录水平的个体定量实时PCR和翻译水平的免疫印迹进行了验证。这些结果在Cd-PWR 1 E与亲本PWR 1 E细胞中是一致的。基因集富集分析显示，五个前列腺癌（PCa）相关的途径富集在镉暴露的细胞相比，他们的正常对照。这些途径包括癌症中的KEGG途径、前列腺癌途径、ERBB、细胞凋亡和MAPK途径。我们从PI 3 K/Akt通路阵列中随机选择上调和下调基因，并在TCGA/GDC前列腺腺癌（PRAD）患者队列中分析这些基因。与正常对照组相比，PCa中的癌基因上调，TS基因下调。综上所述，我们的研究表明，PI 3 K/Akt信号转导是参与镉驱动的正常前列腺上皮细胞转化为恶性形式的主要分子途径之一。了解参与镉驱动的正常前列腺细胞恶性转化的分子机制，将提供一个重要的见解，以制定更好的治疗策略，镉诱导的前列腺癌。
This study investigated the role of the PI3K/Akt pathway in cadmium (Cd) induced malignant transformation of normal prostate epithelial (PWR1E and RWPE1) cells. Both PWR1E and RWPE1 cells were exposed to 10μM Cd for one year and designated as Cd-PWR1E and Cd-RWPE1. Cd-RWPE1 cells robustly formed tumors in athymic nude mice. Functionally, Cd-exposure induced tumorigenic attributes indicated by increased wound healing, migration and invasion capabilities in both cell lines. RT2-array analysis revealed many oncogenes including P110α, Akt, mTOR, NFKB1 and RAF were induced whereas tumor suppressor (TS) genes were attenuated in Cd-RWPE1. This was validated by individual quantitative-real-time-PCR at transcriptional and by immunoblot at translational levels. These results were consistent in Cd-PWR1E vs parental PWR1E cells. Gene Set Enrichment Analysis revealed that five prostate cancer (PCa) related pathways were enriched in Cd-exposed cells compared to their normal controls. These pathways include the KEGG- Pathways in cancer, Prostate Cancer Pathway, ERBB, Apoptosis and MAPK pathways. We selected up- and down-regulated genes randomly from the PI3K/Akt pathway array and profiled these in the TCGA/GDC prostate-adenocarcinoma (PRAD) patient cohort. An upregulation of oncogenes and downregulation of TS genes was observed in PCa compared to their normal controls. Taken together, our study reveals that the PI3K/Akt signaling is one of the main molecular pathways involved in Cd-driven transformation of normal prostate epithelial cells to malignant form. Understanding the molecular mechanisms involved in the Cd-driven malignant transformation of normal prostate cells will provide a significant insight to develop better therapeutic strategies for Cd-induced prostate cancer.
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影响因子：
7.3
作者：
Baiz, Daniele;Pinder, Tanya A.;Hassan, Sazzad;Karpova, Yelena;Salsbury, Freddie;Welker, Mark E.;Kulik, George
通讯作者：
Kulik, George
影响因子：
5.6
作者：
Asara Y;Marchal JA;Carrasco E;Boulaiz H;Solinas G;Bandiera P;Garcia MA;Farace C;Montella A;Madeddu R
通讯作者：
Madeddu R
计算机辅助靶向 PI3K/Akt/mTOR 通路：毒性降低和治疗机会。
影响因子：
5.6
作者：
Li T;Wang G
通讯作者：
Wang G
影响因子：
3.5
作者：
Hartwig, Andrea
通讯作者：
Hartwig, Andrea
影响因子：
11.2
作者：
Julin, Bettina;Wolk, Alicja;Akesson, Agneta
通讯作者：
Akesson, Agneta