4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression
1
Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
2
Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
3
Division of Colorectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei City 110, Taiwan
4
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong 153254, China
5
Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
6
Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
7
Department of Appiled Chemistry, Chaoyang University of Technology, Taichung 41147, Taiwan
8
Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
9
Amoy-BUCT Industrial Bio-Technovation Institute, Amoy 361022, China
10
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
11
Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
12
Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2018, 10(8), 269; https://doi.org/10.3390/cancers10080269
Received: 12 July 2018
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Revised: 4 August 2018
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Accepted: 7 August 2018
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Published: 10 August 2018
Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, Western blot, real-time polymerase chain reaction (RT-PCR), and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-acetylantroquinonol B (4-AAQB), as evidenced by inhibited cell viability and proliferation, as well as attenuated migration, invasion, and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. Interestingly, 4-AAQB did not affect the viability and proliferation of normal colon cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates the FOLFOX (folinate (leucovorin), fluorouracil (5FU), and oxaliplatin) anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324, and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.
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Keywords:
4-AAQB; SOD2; hsa-miR-324; colon cancer stem cells; chemoresistance; chemosensitivity
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Link: http://Supplementary Figure 1. Bioinformatics-based systemic pharmacoanalyses reveal health effect of 4-AAQB.
Description: Figure S1. Bioinformatics-based systemic pharmacoanalyses reveal health effects of 4-AAQB. -
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Link: http://Supplementary Figure 2. 4-AAQB dose determination and ADMET analyses for in vivo assays.
Description: Figure S2. 4-AAQB dose determination and ADMET analyses for in vivo assays.
MDPI and ACS Style
Bamodu, O.A.; Yang, C.-K.; Cheng, W.-H.; Tzeng, D.T.W.; Kuo, K.-T.; Huang, C.-C.; Deng, L.; Hsiao, M.; Lee, W.-H.; Yeh, C.-T. 4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression. Cancers 2018, 10, 269. https://doi.org/10.3390/cancers10080269
AMA Style
Bamodu OA, Yang C-K, Cheng W-H, Tzeng DTW, Kuo K-T, Huang C-C, Deng L, Hsiao M, Lee W-H, Yeh C-T. 4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression. Cancers. 2018; 10(8):269. https://doi.org/10.3390/cancers10080269
Chicago/Turabian StyleBamodu, Oluwaseun A., Ching-Kuo Yang, Wei-Hong Cheng, David T.W. Tzeng, Kuang-Tai Kuo, Chun-Chih Huang, Li Deng, Michael Hsiao, Wei-Hwa Lee, and Chi-Tai Yeh. 2018. "4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by Inducing hsa-miR-324 re-Expression" Cancers 10, no. 8: 269. https://doi.org/10.3390/cancers10080269
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