Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway
Background: Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt can...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-09-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2072-6694/10/10/353 |
| _version_ | 1797725655447633920 |
|---|---|
| author | Szu-Yuan Wu Yan-Jiun Huang Yew-Min Tzeng Chi-Ying F. Huang Michael Hsiao Alexander T.H. Wu Tse-Hung Huang |
| author_facet | Szu-Yuan Wu Yan-Jiun Huang Yew-Min Tzeng Chi-Ying F. Huang Michael Hsiao Alexander T.H. Wu Tse-Hung Huang |
| author_sort | Szu-Yuan Wu |
| collection | DOAJ |
| description | Background: Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt cancer stemness signaling, may provide improved therapeutic efficacy. Methods: Mimicking the tumor microenvironment, we treated colon cancer cells with exogenous IGF1. The increased stemness of IGF1-cultured cells was determined by ALDH1 activity, side-population, tumor sphere formation assays. Destruxin B (DB) was evaluated for its anti-tumorigenic and stemness properties using cellular viability, colony-formation tests. The mimic and inhibitor of miR-214 were used to treat colon cancer cells to show its functional association to DB treatment. In vivo mouse models were used to evaluate DB’s ability to suppress colon tumor-initiating ability and growth inhibitory function. Results: IGF1-cultured colon cancer cells showed a significant increase in 5-FU resistance and enhanced stemness properties, including an increased percentage of ALDH1+, side-population cells, tumor sphere generation in vitro, and increased tumor initiation in vivo. In support, using public databases showed that increased IGF1 expression was significantly associated with a poorer prognosis in patients with colon cancer. DB, a hexadepsipeptide mycotoxin, was able to suppress colon tumorigenic phenotypes, including colony and sphere formation. The sequential treatment of DB, followed by 5-FU, synergistically inhibited the viability of colon cancer cells. In vivo studies showed that DB suppressed the tumorigenesis by 5-FU resistant colon cells, and in a greater degree when combined with 5-FU. Mechanistically, DB treatment was associated with decreased the mammalian target of rapamycin (mTOR) and β-catenin expression and an increased miR-214 level. Conclusion: We provided evidence of DB as a potential therapeutic agent for overcoming 5-FU resistance induced by IGF1, and suppressing cancer stem-like properties in association with miR-214 regulation. Further investigation is warranted for its translation to clinical application. |
| first_indexed | 2024-03-12T10:34:24Z |
| format | Article |
| id | doaj.art-2bbc9cd07a0446e4a9d410c781053ca8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:34:24Z |
| publishDate | 2018-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2bbc9cd07a0446e4a9d410c781053ca82023-09-02T08:51:32ZengMDPI AGCancers2072-66942018-09-01101035310.3390/cancers10100353cancers10100353Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin PathwaySzu-Yuan Wu0Yan-Jiun Huang1Yew-Min Tzeng2Chi-Ying F. Huang3Michael Hsiao4Alexander T.H. Wu5Tse-Hung Huang6Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei 116, TaiwanDivision of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, TaiwanDepartment of Life Science, National Taitung University, Taitung 950, TaiwanInstitute of Biopharmaceutical Sciences, National Yang Ming University, Taipei 112, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanThe PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 115, TaiwanDepartment of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 204, TaiwanBackground: Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt cancer stemness signaling, may provide improved therapeutic efficacy. Methods: Mimicking the tumor microenvironment, we treated colon cancer cells with exogenous IGF1. The increased stemness of IGF1-cultured cells was determined by ALDH1 activity, side-population, tumor sphere formation assays. Destruxin B (DB) was evaluated for its anti-tumorigenic and stemness properties using cellular viability, colony-formation tests. The mimic and inhibitor of miR-214 were used to treat colon cancer cells to show its functional association to DB treatment. In vivo mouse models were used to evaluate DB’s ability to suppress colon tumor-initiating ability and growth inhibitory function. Results: IGF1-cultured colon cancer cells showed a significant increase in 5-FU resistance and enhanced stemness properties, including an increased percentage of ALDH1+, side-population cells, tumor sphere generation in vitro, and increased tumor initiation in vivo. In support, using public databases showed that increased IGF1 expression was significantly associated with a poorer prognosis in patients with colon cancer. DB, a hexadepsipeptide mycotoxin, was able to suppress colon tumorigenic phenotypes, including colony and sphere formation. The sequential treatment of DB, followed by 5-FU, synergistically inhibited the viability of colon cancer cells. In vivo studies showed that DB suppressed the tumorigenesis by 5-FU resistant colon cells, and in a greater degree when combined with 5-FU. Mechanistically, DB treatment was associated with decreased the mammalian target of rapamycin (mTOR) and β-catenin expression and an increased miR-214 level. Conclusion: We provided evidence of DB as a potential therapeutic agent for overcoming 5-FU resistance induced by IGF1, and suppressing cancer stem-like properties in association with miR-214 regulation. Further investigation is warranted for its translation to clinical application.http://www.mdpi.com/2072-6694/10/10/353colon cancerdestruxin Bcancer stem-like cells5-FU resistancemTOR/β-catenin signaling and miR-214 |
| spellingShingle | Szu-Yuan Wu Yan-Jiun Huang Yew-Min Tzeng Chi-Ying F. Huang Michael Hsiao Alexander T.H. Wu Tse-Hung Huang Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway Cancers colon cancer destruxin B cancer stem-like cells 5-FU resistance mTOR/β-catenin signaling and miR-214 |
| title | Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway |
| title_full | Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway |
| title_fullStr | Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway |
| title_full_unstemmed | Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway |
| title_short | Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway |
| title_sort | destruxin b suppresses drug resistant colon tumorigenesis and stemness is associated with the upregulation of mir 214 and downregulation of mtor β catenin pathway |
| topic | colon cancer destruxin B cancer stem-like cells 5-FU resistance mTOR/β-catenin signaling and miR-214 |
| url | http://www.mdpi.com/2072-6694/10/10/353 |
| work_keys_str_mv | AT szuyuanwu destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway AT yanjiunhuang destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway AT yewmintzeng destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway AT chiyingfhuang destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway AT michaelhsiao destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway AT alexanderthwu destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway AT tsehunghuang destruxinbsuppressesdrugresistantcolontumorigenesisandstemnessisassociatedwiththeupregulationofmir214anddownregulationofmtorbcateninpathway |