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

Jyoti B Kaushal, Kaushal JB, Jyoti Kaushal, Vinay Shukla, Sankhwar P, Pushplata Sankhwar, Rajesh Kumar Jha, Rajesh K Jha, Jha RK, Dwivedi A, Anila Dwivedi
Cytokine · 2021 · vol. 148 , pp. 155700 · doi:10.1016/j.cyto.2021.155700 · PMID:34560609 · W3199209690
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Targeted inhibition of TAK1 abrogated TGFβ1 non-canonical signaling, suppressed NFκB/Smad7, and reduced human endometriotic cell proliferation while inducing autophagy-involved cell death.

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Abstract

Transforming growth factor (TGFβ) 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 TGFβ1- induced cellular responses and delineated the signaling mechanism in human endometriotic cells. The endometriotic cells showed elevated expression of TGFβ1 signaling-effector molecules. TGFβ1 exposure to endometriotic cells induced the expression of the downstream target molecules indicating that TGFβ1 is implicated in the commencement ofTAK1/NFκB-p65/Smad7 cascade. The silencing of TAK1 in endometriotic cells attenuated the TGFβ1 -induced NFκB transcriptional activation and nuclear translocation of NFκB-p65 subunit. The pharmacological inhibition of NFκB 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 TGFβ1. The inhibition of TAK1 attenuated the TGFβ1 signaling activation indicating that TAK1 is a crucial mediator for TGFβ1 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 TGFβ1 and NFκB-p65 that promotes the growth and inflammatory response in endometriotic cells.

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Condition tags

endometriosis

MeSH descriptors

Autophagy Autophagy Autophagy Endometriosis Endometriosis MAP Kinase Kinase Kinases NF-kappa B Signal Transduction Signal Transduction Signal Transduction Smad7 Protein Transforming Growth Factor beta1 Apoptosis Apoptosis Apoptosis Cell Cycle Checkpoints Cell Cycle Checkpoints Cell Cycle Checkpoints Cell Death Cell Death

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