The role of mitogen‐activated protein kinase signaling pathway in endometriosis

Abstract

Aim Endometriosis is an estrogen‐dependent chronic inflammatory condition which causes pain, infertility, and predisposition for ovarian cancer. Endometriosis generates a unique microenvironment for survivability of endometriotic lesions which includes cell proliferation, differentiation, migration, and apoptosis. For these cellular activities, cascading activations of intracellular kinases are needed. Many kinase signaling pathways, IKKβ/NK‐κB pathway, PI3K/AKT/mTOR, and the mitogen‐activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK), are activated in endometriosis. In this review, we focus on the role of MAPK pathways in endometriosis. Methods To identify the role of MAP Kinase signaling pathway in endometriosis we searched the Pubmed database using the search terms in various combinations “endometriosis,” “endometrium,” “ovary,” “MAPK pathway,” “ERK pathway,” “p38 pathway,” “JNK pathway,” “estrogen,” and “progesterone.” Results According to the current literature, MAPK signaling pathway has various roles in generating microenvironment and survival of endometriosis. Abnormal MAPK activation in migration, implantation, growth, invasion into the pelvic structures, proliferation, and apoptosis leads to the form of endometriosis and to worsen the condition in patients with endometriosis. Conclusion To further investigations on the effective and long‐term endometriosis treatment, MAPK signaling pathways may be targeted. Molecular mechanism of MAPK signaling pathway in endometriosis should be more deeply understood and clinical trials should be more commonly performed for possible new endometriosis treatments to improve fertility and rescue endometriosis irreversibly.

Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

“…Recent studies have emphasized the importance of the MAPK cascade in the development and progression of endometriosis, due to its well-known involvement in the regulation of proliferation, gene expression, differentiation, mitosis, inflammation and survival/apoptosis [32,36,37]. MAPKs are part of the serine/threonine kinases and include three subfamilies that are distinguished by their biological function: Extracellular signal-Regulated Kinases (ERKs) [38] acting on the control of cell division, c-Jun N-terminal Kinases (JNKs) [39], involved in transcription regulation, and, finally, p38 mitogen-activated protein kinases (p38s) [40], that play a role in immune response, cell survival and differentiation.…”

“…A detailed description of the studies that have evaluated the MAPK signaling in endometriotic lesions is presented elsewhere [37]. In general, this signaling has been suggested to favour the disease establishment via several mechanisms: 1.…”

Localização de células senescentes nas lesões de pacientes com endometriose profunda

“…(95) Uma vez ativada, as MAPKs iniciam uma resposta celular por meio de fatores de transcrição nuclear, como transdutor de sinal e ativador de transcrição 1 (STAT1), fator de transcrição nuclear (CREB), fator de transcrição ativador 2 (ATF-2), e c-Jun que em combinação com c-fos formam a proteína ativadora 1 (AP-1) e p53. (95) Na endometriose, estudos mostram uma desregulação nas vias MAPK, (96,97) sendo através da ERK, (98) da p38 (99) ou JNK. (100) A ativação das vias MAPK seguem uma tripla cascata de eventos que culminam com a ativação dos fatores de transcrição nucleares descritos acima.…”

“…As vias de sinalização MAPK podem possuir formas distintas de atuação na resposta inflamatória da endometriose. (97) A via mediada por ERK, está envolvida ao crescimento, proliferação e sobrevivência celular. (96,98) A MAPK p38, tem um papel central e crítico na regulação de várias doenças imunológicas e está associada a inflamação, crescimento celular, diferenciação e morte celular.…”

“…(ERO) (93) e também sua relação com um dos principais sintomas, a dor pélvica, demonstrando que a inibição de ERK1/2 reduz a expressão de P2X3, um receptor sensorial. (97,202,203) Na senescência, a estimulação aguda de fibroblastos com irradiação aumentou a expressão de p38MAPK, uma das principais quinases da via MAPK e sua proteína final HSP27. Os autores afirmaram que, apesar de responder apenas ao estresse agudo, a p38MAPK possui uma cinética de ativação semelhante ao de SASP.…”