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

• Published in: Cancers 2018-08, Vol.10 (8), p.269
• Main Authors: Bamodu, Oluwaseun Adebayo, Yang, Ching-Kuo, Cheng, Wei-Hong, Tzeng, David T W, Kuo, Kuang-Tai, Huang, Chun-Chih, Deng, Li, Hsiao, Michael, Lee, Wei-Hwa, Yeh, Chi-Tai
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Bcl-x protein; Bioinformatics; c-Myc protein; Cancer therapies; Cell proliferation; Chemoresistance; Colorectal cancer; Colorectal carcinoma; Data processing; Dehydrogenases; DNA methylation; E-cadherin; Epigenetics; Gene expression; Genetic factors; Genotype & phenotype; Hospitals; Kinases; Medicine; Metastases; Metastasis; MicroRNAs; miRNA; Morbidity; Myc protein; N-Cadherin; Oxaliplatin; Oxidative stress; Phenotypes; Polymerase chain reaction; Proteins; Stem cells; Superoxide dismutase; Surgery; Thoracic surgery; Tumorigenicity; Vimentin
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers10080269

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. 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. 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. 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.