Oncotarget

Research Papers:

NFkB is essential for activin-induced colorectal cancer migration via upregulation of PI3K-MDM2 pathway

Arundhati Jana, Nancy L. Krett, Grace Guzman, Ahmer Khalid, Ozkan Ozden, Jonas J. Staudacher, Jessica Bauer, Seung Hyun Baik, Timothy Carroll, Cemal Yazici and Barbara Jung _

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Oncotarget. 2017; 8:37377-37393. https://doi.org/10.18632/oncotarget.16343

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Abstract

Arundhati Jana1, Nancy L. Krett1, Grace Guzman2, Ahmer Khalid1, Ozkan Ozden1, Jonas J. Staudacher1, Jessica Bauer1, Seung Hyun Baik1, Timothy Carroll1, Cemal Yazici1 and Barbara Jung1

1Division of Gastroenterology and Hepatology, University of Illinois Medical College, Chicago, IL 60612, USA

2Department of Pathology, University of Illinois Medical College, Chicago, IL 60612, USA

Correspondence to:

Barbara Jung, email: [email protected]

Keywords: activin, NFkB, colon cancer, MDM2, migration

Received: September 07, 2016    Accepted: February 09, 2017    Published: March 18, 2017

ABSTRACT

Colorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Activin and TGFB (TGFβ) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. We have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs. To investigate the mechanism of metastatic activin signaling, we examined activated NFkB signaling and activin ligand expression in CRC patient samples and found a strong correlation. We hypothesize that activation of the E3 ubiquitin ligase MDM2 by NFkB leads to p21 degradation in response to activin treatment. To dissect the link between activin and pro-carcinogenic NFkB signaling and downstream targets, we found that activin but not TGFB induced activation of NFkB leading to increased MDM2 ubiquitin ligase via PI3K. Further, overexpression of wild type p65 NFkB increased MDM2 expression while the NFkB inhibitors NEMO-binding domain (NBD) and Bay11-7082 blocked the activin-induced increase in MDM2. In conclusion, in colon cancer cell migration, activin utilizes NFkB to induce MDM2 activity leading to the degradation of p21 in a PI3K dependent mechanism. This provides new mechanistic knowledge linking activin and NFkB signaling in advanced colon cancer which is applicable to targeted therapeutic interventions.


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