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

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.

A miR-29b Byproduct Sequence Exhibits Potent Tumor-Suppressive Activities via Inhibition of NF-κB Signaling in KRAS-Mutant Colon Cancer Cells

“…9, 13, 44). As mentioned in Introduction, NF-kB is activated in KRAS-mutated colorectal cancer (9,10). We indeed demonstrated that MIRTX could directly bind to the 3 0 -UTR region of CXCR2 and PIK3R1 mRNAs and suppress protein expression of both genes in KRAS-mutated colorectal cancer cells, DLD1 and SW480.…”

“…Recent evidence indicates that the NF-kB transcription factor is constitutively activated in KRAS-mutant colorectal cancer (9,10). Therefore, targeting NF-kB signaling pathway represents a promising strategy against KRAS-mutant colorectal cancer, although this has not been successful so far in colorectal cancer.…”

Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways

“…Inhibition of NF-κB could repress these chemokines, such as MCP-1, VEGF, IL-8 and Gro-α [138][139][140][141]. Moreover, PI3K promoted the transcription of MDM2 and degradation of p21 in an NF-κB-dependent manner, which can promote colon cancer cell migration [142].…”

Nuclear Factor I A Promotes Temozolomide Resistance in Glioblastoma via Transcriptional Regulation of Nuclear Factor κB Pathway

“…Nuclear Factor κB (NF-κB) pathway is well known for its variety of functions on cellular responses and disease development. Abnormal activation of NF-κB pathway mediates a wide range of cellular processes related to tumorigenesis, including reduction of cell apoptosis, oncogene mutations and immune stimulation in multiple types of human cancers [8][9][10]. Activation of NF-κB in cancers is most likely though either inflammatory stimulation such as tumor necrosis factor (TNF) or upstream regulator such as NF-kB-inducing kinase (NIK), respectively [11,12].…”