Synergistic interaction between AKT and Notch-1 signaling in cervical cancer: a critical role in tumor cell migration and invasion

Received September 23, 2016; Accepted February 09, 2017; Published March 12, 2017
http://dx.doi.org/10.18081/2333-5106/017-45-59   

Willem B. Doshi, Peter G. Thury,  Rui Chen, Jone A. Fishbein,  Micheal K. Foley

Abstract

Cervical cancer (CC) is the second most common malignant tumor in women all over the world and is also a major cause of cancer-related death in developing countries, especially in Asia and Africa. Metastasis is a leading cause of death in patients with cervical carcinoma and is a complex biological process involving detachment, migration, invasion, intravasation into and circulation in lymphovasculature, migration, invasion, adhesion, and growth within distant lymph nodes and distant organs. The phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway is a key factor in promoting the migration and invasion of many tumors, including endometrial, ovarian, and lung cancers. Thus, a better understanding of the molecular mechanisms downstream of HPV viral infection would be pivotal in designing improved therapies against cervical cancer. The PI3-K/AKT pathway is frequently activated in cervical cancer, but the key factors in its downstream signaling have yet to be revealed. Therefore, a more in-depth analysis of AKT signaling is essential in order to fully exploit the potential of this pathway as a therapeutic target. Expression of NICD1 is frequently observed in cervical cancer and has been suggested to be oncogenic. Herein, we demonstrate that N1ICD significantly upregulated expression of the Notch target genes Hes1 and Hey1 in the context of reduced AKT activity. Our data support a revised model in which AKT signaling can modulate the oncogenic potential of N1ICD in cervical cancer, thus substantially influencing the effectiveness of both the PI3K and Notch signaling pathways in this clinical setting.

Key words: Cervical cancer, Notch signaling, AKT, NF-κB, IKK activation

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