Journal
CELL DEATH & DISEASE
Volume 11, Issue 12, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-020-03235-w
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Funding
- NIH-NIMHD [U54MD007598]
- Department-of-Defense Breast Cancer Research Program [BC043180]
- NIH/NCATS CTSI [UL1TR000124]
- Accelerating Excellence in Translational Science Pilot Grants [G0812D05, G0814C01]
- NIH/NIGMS [1SC1GM121202]
- NIH/NCI [1SC2CA235066, SC1CA200517, 9 SC1 GM135050-05, 1U54CA14393, U56 CA101599-01]
- CSUPERB
- Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai [PWZxq2017-13]
- International Postdoctoral Fellowship Program [20150069]
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The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.
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