Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA
Abstract 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 Comp3...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2020-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03235-w |
| _version_ | 1818329676738723840 |
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| author | Qiongyu Hao Piwen Wang Pranabananda Dutta Seyung Chung Qun Li Kun Wang Jieqing Li Wei Cao Wenhong Deng Qing Geng Katrina Schrode Magda Shaheen Ke Wu Donghui Zhu Qiao-Hong Chen Guanglin Chen Yahya Elshimali Jay Vadgama Yong Wu |
| author_facet | Qiongyu Hao Piwen Wang Pranabananda Dutta Seyung Chung Qun Li Kun Wang Jieqing Li Wei Cao Wenhong Deng Qing Geng Katrina Schrode Magda Shaheen Ke Wu Donghui Zhu Qiao-Hong Chen Guanglin Chen Yahya Elshimali Jay Vadgama Yong Wu |
| author_sort | Qiongyu Hao |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-13T12:51:51Z |
| format | Article |
| id | doaj.art-0cda7630fbaa4ff8a34e820f33a0a735 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-13T12:51:51Z |
| publishDate | 2020-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-0cda7630fbaa4ff8a34e820f33a0a7352022-12-21T23:45:18ZengNature Publishing GroupCell Death and Disease2041-48892020-12-01111211810.1038/s41419-020-03235-wComp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNAQiongyu Hao0Piwen Wang1Pranabananda Dutta2Seyung Chung3Qun Li4Kun Wang5Jieqing Li6Wei Cao7Wenhong Deng8Qing Geng9Katrina Schrode10Magda Shaheen11Ke Wu12Donghui Zhu13Qiao-Hong Chen14Guanglin Chen15Yahya Elshimali16Jay Vadgama17Yong Wu18Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDepartment of Oncology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Breast Cancer, Cancer Center, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical SciencesDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDepartment of Thoracic Surgery, Renmin Hospital of Wuhan UniversityDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDepartment of Biomedical Engineering, Stony Brook UniversityDepartment of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterDivision of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer CenterAbstract 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.https://doi.org/10.1038/s41419-020-03235-w |
| spellingShingle | Qiongyu Hao Piwen Wang Pranabananda Dutta Seyung Chung Qun Li Kun Wang Jieqing Li Wei Cao Wenhong Deng Qing Geng Katrina Schrode Magda Shaheen Ke Wu Donghui Zhu Qiao-Hong Chen Guanglin Chen Yahya Elshimali Jay Vadgama Yong Wu Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA Cell Death and Disease |
| title | Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA |
| title_full | Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA |
| title_fullStr | Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA |
| title_full_unstemmed | Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA |
| title_short | Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA |
| title_sort | comp34 displays potent preclinical antitumor efficacy in triple negative breast cancer via inhibition of nudt3 as4 a novel oncogenic long noncoding rna |
| url | https://doi.org/10.1038/s41419-020-03235-w |
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