Can we Inhibit the Survival of Endometriosis?

ERK1/2 and AKT Pathways in Endometriosis

Key Points

Highlight:

• Dr. Banu group suggests that dual inhibition of ERK1/2 and AKT pathways can be a potential non-steroidal therapy for the treatment of endometriosis.

Background:

• An extracellular signal-regulated kinase (ERK1/2), phosphatidylinositide 3-kinase (PI3K), and protein kinase B (AKT) are the well-studied survival pathways which regulate proliferation, survival, and apoptosis of the cells by integrating multiple intracellular signaling modules.
• A relatively small number of studies have demonstrated the molecular link between endometriosis and ERK1/2 or AKT pathways, including Dr. Banu group.
• No studies have reported the effects of combined inhibition of ERK1/2 and AKT pathways in endometriosis.
• In this paper, the author suggests that the partial growth inhibitory or apoptotic effect is due to the compensatory mechanisms between the ERK1/2 and AKT pathways and dual inhibition may have synergistic effect in treating endometriosis.

Key points:

• Cell signaling pathway analysis confirmed the existence compensatory interactions between ERK1/2 and AKT pathways.
• Dual inhibition of ERK1/2 and AKT pathways regulates multiple transcriptional factors in an epithelial-stromal cell-specific and pathway-dependent pathway in human endometriotic cells and the combined inhibition significantly inhibits cell proliferation, then single inhibition.
• Cell cycle analysis indicates that inhibition of ERK1/2 and AKT pathways dysregulates cell cycle regulatory proteins involved in G1-S and G2-M transition in an epithelial and stromal cell-specific and pathway-dependent pattern.
• Furthermore, the combined inhibition of ERK1/2 and AKT pathways activates intrinsic apoptosis mechanisms and increases cell death in human endometriotic cells.

Conclusions:

• This study collectively indicates that inhibition of ERK1/2 and AKT pathways decreases the growth and survival of endometriotic cells through multiple mechanisms.
• Dual inhibition of the ERK1/2 and AKT pathways can be a potential non-steroidal therapy for the treatment of endometriosis in women.

Lay Summary

Endometriosis is an estrogen-dependent gynecological inflammatory disease. The current anti-estrogen therapies can be prescribed only for a short time due to the undesirable side effects on menstruation, pregnancy, bone health, and recurrence. Therefore, the development of specific therapy which targets abnormal molecular pathways in endometriosis is highly required.

ERK1/2 and PI3K-AKT are the well-studied survival pathways which regulate proliferation, survival, and apoptosis of the cells by integrating multiple intracellular signaling modules. The role of ERK1/2 or AKT signaling in proliferation, growth, and survival is well studied in a variety of cells, but not in endometriosis. In early 2009, the authors of this article (Dr. Banu group) reported that ERK1/2 and AKT pathways are highly activated in the epithelial and stromal cells of endometriotic lesions. Other researchers have found that inhibition of ERK1/2 or AKT pathway partially decreased proliferation and viability of human endometriotic stromal cells. However, the effect of combined inhibition of ERK1/2 and AKT pathways in endometriosis has not been well-studied. In this paper, published in Molecular and Cellular Endocrinology, Dr. Banu group suggests that the dual inhibition of ERK1/2 and AKT pathways have synergistic effects in targeting endometriosis.

To understand the dual role of ERK1/2 and AKT pathways in the pathogenesis of endometriosis, authors first determined their interactive cell signaling pathways. Cell signaling pathway analysis confirmed the existence compensatory interactions between ERK1/2 and AKT pathways. Dual inhibition of ERK1/2 and AKT pathways regulates multiple transcriptional factors in an epithelial-stromal cell-specific and pathway-dependent pathway in human endometriotic cells. In both epithelial and stromal cells, the combined inhibition of ERK1/2 and AKT pathways significantly inhibits cell proliferation and dysregulate the cell cycle. Furthermore, the combined inhibition of ERK1/2 and AKT pathways activates intrinsic apoptosis mechanisms and this leads an increased cell death in human endometriotic cells.

In conclusion, this study collectively indicates that inhibition of ERK1/2 and AKT pathways decreases the growth and survival of endometriotic cells through multiple mechanisms. Based on the results, authors believe that dual inhibition of ERK1/2 and AKT pathways can be a potential non-steroidal therapy for the treatment of endometriosis in women.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/30578826