EGFR/MDM2 signaling promotes NF-{kappa}B activation via PPAR{gamma} degradation

Dysregulated expression of epidermal growth factor receptor (EGFR) has been implicated in many cancer events, while peroxisome proliferator-activated receptor (PPAR) negatively regulates cancer progression. The molecular mechanism of EGFR interaction with PPAR is still unclear. Here, we found that nuclear EGFR induced phosphorylation of PPAR at Tyr-74 leading to PPAR ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase. PPAR degradation by EGFR/MDM2 signaling resulted in accumulation of nuclear factor-kappaB (NF-B)/p65 protein levels and increasing NF-B activation. In contrast, PPAR–Y74A mutant reversed this event. Moreover, PPAR–Y74A mutant suppressed cell proliferation and increased chemotherapeutic agent-induced cancer cell sensitivity. Importantly, the clinical findings show that the nuclear phosphorylation of PPAR–Y74 and EGFR expression in colonic cancer tissues was higher than that in control normal tissues. Thus, our study revealed a novel molecular mechanism that nuclear EGFR/NF-B signaling promoted cell proliferation by destructing PPAR function, which provides a novel strategy for cancer treatment.

Source: Carcinogenesis - February 8, 2016 Category: Cancer & Oncology Authors: Xu, Y., Jin, J., Zhang, W., Zhang, Z., Gao, J., Liu, Q., Zhou, C., Xu, Q., Shi, H., Hou, Y., Shi, J. Tags: Original Manuscript Source Type: research