Inhibitory Role of TRIP-Br1/XIAP in Necroptosis under Nutrient/Serum Starvation
Zolzaya Sandag1,2, Samil Jung1,2, Nguyen Thi Ngoc Quynh1, Davaajargal Myagmarjav1, Nguyen Hai Anh1, Dan-Diem Thi Le1, Beom Suk Lee1, Raj Kumar Mongre1, Taeyeon Jo1, and MyeongSok Lee1,*
1Department of Biological Science, Sookmyung Women’s University, Seoul 14310, Korea, 2These authors contributed equally to this work.
Received August 27, 2019; Revised December 19, 2019; Accepted January 2, 2020.; Published online February 13, 2020.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

Currently, many available anti-cancer therapies are targeting apoptosis. However, many cancer cells have acquired resistance to apoptosis. To overcome this problem, simultaneous induction of other types of programmed cell death in addition to apoptosis of cancer cells might be an attractive strategy. For this purpose, we initially investigated the inhibitory role of TRIP-Br1/XIAP in necroptosis, a regulated form of necrosis, under nutrient/serum starvation. Our data showed that necroptosis was significantly induced in all tested 9 different types of cancer cell lines in response to prolonged serum starvation. Among them, necroptosis was induced at a relatively lower level in MCF-7 breast cancer line that was highly resistant to apoptosis than that in other cancer cell lines. Interestingly, TRIP-Br1 oncogenic protein level was found to be very high in this cell line. Upregulated TRIP-Br1 suppressed necroptosis by repressing reactive oxygen species generation. Such suppression of necroptosis was greatly enhanced by XIAP, a potent inhibitor of apoptosis. Our data also showed that TRIP-Br1 increased XIAP phosphorylation at serine87, an active form of XIAP. Our mitochondrial fractionation data revealed that TRIPBr1 protein level was greatly increased in the mitochondria upon serum starvation. It suppressed the export of CypD, a vital regulator in mitochondria-mediated necroptosis, from mitochondria to cytosol. TRIP-Br1 also suppressed shikoninmediated necroptosis, but not TNF-α-mediated necroptosis, implying possible presence of another signaling pathway in necroptosis. Taken together, our results suggest that TRIPBr1/XIAP can function as onco-proteins by suppressing necroptosis of cancer cells under nutrient/serum starvation.
Keywords: necroptosis, programmed cell death, TRIP-Br1, XIAP

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31 January 2020 Volume 43,
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