Targeted inhibition of TAK1 abrogates TGFβ1 non-canonical signaling axis, NFκB/Smad7 inhibiting human endometriotic cells proliferation and inducing cell death involving autophagy

Transforming growth factor (TGF beta) is known to play a major role in establishment and maintenance of endometriosis as reported by our group earlier, the underlying mechanism remains to be explored. We deciphered the involvement of TAK1 in TGF beta 1- induced cellular responses and delineated the signaling mechanism in human endometriotic cells. The endometriotic cells showed elevated expression of TGF beta 1 signaling-effector molecules. TGF beta 1 exposure to endometriotic cells induced the expression of the downstream target molecules indicating that TGF beta 1 is implicated in the commencement ofTAK1/NF kappa B-p65/Smad7 cascade. The silencing of TAK1 in endometriotic cells attenuated the TGF beta 1 -induced NF kappa B transcriptional activation and nuclear translocation of NF kappa B-p65 subunit. The pharmacological inhibition of NFXB by QNZ or knockdown of TAK1 reduced the expression of Smad7 and Cox2. The knockdown of TAK1 in endometriotic cells showed G1 phase cell-cycle arrest and showed low BrdU-incorporation in the presence of TGF beta 1. The inhibition of TAK1 attenuated the TGF beta 1 signaling activation indicating that TAK1 is a crucial mediator for TGF beta 1 action in endometriotic cells. The exposure of endometriotic cells to TAK1 inhibitor, celastrol caused activation of caspase-3 and -9 that led to PARP cleavage and induced apoptosis. Simultaneously, autophagy occurred in celastrol-treated and TAK1-silenced cells as was evidenced by the formation of autophagosome and the increased expression of autophagic markers. Thus, TAK1 activation appears to protect the growth of endometriotic cells by suppressing the cell death process. Overall, our study provided the evidence that of TAK1 significant in the endometriotic cell regulation and mediates a functional cross-talk between TGF beta 1 and NF kappa B-p65 that promotes the growth and inflammatory response in endometriotic cells.

Automated summary

The study uncovered the crucial role of TAK1 in mediating TGF beta 1-induced responses in endometriotic cells, influencing the activation of the NF kappa B-p65/Smad7 signaling cascade and subsequently affecting cell growth and inflammatory responses.