Regulation of P21-Activated Kinase-4 by Progesterone and Tumor Necrosis Factor-α in Human Endometrium and Its Increased Expression in Advanced-Stage Endometriosis

Context: Endometriosis is a common gynecological condition characterized by enhanced proliferation, adhesiveness, invasiveness, and survival of endometrial cells after retrograde menstruation. Originally identified as a cytoskeletal regulatory kinase, p21-activated kinase 4 (Pak4) regulates diverse cellular activities that might be altered in the establishment and progression of endometriosis. Objective: The aim was to evaluate the effects of sex steroids and proinflammatory cytokines on the Pak4 expression in endometrial cells along with the functional change caused by inhibition of Pak4 expression as well as to see whether the Pak4 expression is altered in endometriosis. Methods: Pak4 expression was analyzed using immunohistochemistry and Western blot analysis. Viability and invasiveness were assayed after transfection of endometrial cells with Pak4 small interfering RNA. Results: The Pak4 expression was significantly decreased in the stromal cells during the secretory phase as well as by in vitro treatment with progesterone. The immunoreactivity of Pak4 was significantly increased in the eutopic endometrium as well as in the ovarian endometriotic cyst of women with endometriosis compared with the control subjects. TNF-alpha induced a significant increase in the Pak4 expression in endometrial cells in vitro, whereas IL-1 beta had no effects. Transfection of endometrial cells with Pak4 small interfering RNA led to a significant decrease in viability and invasiveness in endometrial cells. Conclusion: These findings suggest that Pak4 is regulated by progesterone and TNF-alpha in endometrial cells and that the increased expression of Pak4 might lead to the establishment and progression of endometriosis by enhanced cellular viability and invasiveness in endometrial cells. (J Clin Endocrinol Metab 98: E238-E248, 2013)