RESUMEN
Chronic inflammation is a hallmark of many cancers, yet the pathogenic mechanisms that distinguish cancer-associated inflammation from benign persistent inflammation are still mainly unclear. Here, we report that the protein kinase ERK5 controls the expression of a specific subset of inflammatory mediators in the mouse epidermis, which triggers the recruitment of inflammatory cells needed to support skin carcinogenesis. Accordingly, inactivation of ERK5 in keratinocytes prevents inflammation-driven tumorigenesis in this model. In addition, we found that anti-ERK5 therapy cooperates synergistically with existing antimitotic regimens, enabling efficacy of subtherapeutic doses. Collectively, our findings identified ERK5 as a mediator of cancer-associated inflammation in the setting of epidermal carcinogenesis. Considering that ERK5 is expressed in almost all tumor types, our findings suggest that targeting tumor-associated inflammation via anti-ERK5 therapy may have broad implications for the treatment of human tumors.
Asunto(s)
Carcinogénesis/genética , Inflamación/genética , Proteína Quinasa 7 Activada por Mitógenos/biosíntesis , Neoplasias Cutáneas/genética , Animales , Carcinógenos/toxicidad , Epidermis/metabolismo , Epidermis/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación/inducido químicamente , Inflamación/complicaciones , Inflamación/patología , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Transgénicos , Proteína Quinasa 7 Activada por Mitógenos/genética , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patologíaRESUMEN
Activation of the extracellular-regulated protein kinase 5 (ERK5) has been associated with mitogenic signal transduction. However, conflicting findings have challenged the idea that ERK5 is a critical regulator of cell proliferation. We have addressed this issue by testing the effect of the conditional loss of ERK5 in primary fibroblasts. We have discovered that ERK5 suppressed the expression of the cyclin dependent protein kinase (CDKs) inhibitors, p21 and p27, by decreasing mRNA and protein stability, respectively. As a result, low level CDK2 activity detected in ERK5-deficient cells correlated with a defect in G1 to S phase transition of the cell cycle. Similarly, we found that the malignant MDA-MB-231 human breast cancer cell line was dependent on ERK5 to proliferate. We propose that ERK5 blocks p21 expression in MDA-MB-231 cells via a mechanism that implicates c-Myc-dependent transcriptional regulation of the miR-17-92 cluster. Together with evidence that cancer patients with poor prognosis display a high level of expression of components of the ERK5 signaling pathway, these findings support the hypothesis that ERK5 can be a potential target for cancer therapy.