![]() Although localized forms of CRC can be effectively managed, no curative treatment is currently available for metastatic CRC. This provides new mechanistic knowledge linking activin and NFkB signaling in advanced colon cancer which is applicable to targeted therapeutic interventions.Ĭolorectal cancer (CRC) remains one of the most common types of cancer and constitutes a leading cause of cancer death worldwide due to its high incidence and mortality through advanced stage presentation. 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. 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. 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. We hypothesize that activation of the E3 ubiquitin ligase MDM2 by NFkB leads to p21 degradation in response to activin treatment. 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 have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs. Activin and TGFB (TGFβ) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. Received: SeptemAccepted: FebruPublished: March 18, 2017Ĭolorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Staudacher 1, Jessica Bauer 1, Seung Hyun Baik 1, Timothy Carroll 1, Cemal Yazici 1 and Barbara Jung 1ġDivision of Gastroenterology and Hepatology, University of Illinois Medical College, Chicago, IL 60612, USAĢDepartment of Pathology, University of Illinois Medical College, Chicago, IL 60612, USAīarbara Jung, email: activin, NFkB, colon cancer, MDM2, migration Krett 1, Grace Guzman 2, Ahmer Khalid 1, Ozkan Ozden 1, Jonas J.
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