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Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling.

ABSTRACT: BACKGROUND:Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and developed drug resistance has represented one of the most challenging tasks for management. The current therapeutic regimens may select and enrich cancer stem-like cells (CSCs) resulting in the increased resistance against treatment, metastatic potential and mortality. Regorafenib is a multi-kinase inhibitor, an FDA-approved last-of-line treatment for patients with chemo-refractory metastatic CRC. However, regorafenib's potential effects on CSCs have not been fully elucidated. METHODS:Here, we developed two 5-FU resistant CRC cell lines, HCT-116R and DLD-1R and showed the increased CSCs characteristics such as increased side-population cells, tumor sphere formation and expression of stemness markers. These cell lines and CSCs properties were used for evaluating the potential of regorafenib in suppressing CSCs. RESULTS:We showed that regorafenib treatment decreased the stemness phenotypes including tumor sphere formation, and side-population, of both HCT-116R and DLD-1R cells. Additionally, regorafenib suppressed the cell viability in both cell lines synergistically with 5-FU. In vivo, the combination of regorafenib and 5-FU significantly suppressed the tumorigenesis and stemness markers of 5-FU resistant DLD-1R. Mechanistically, regorafenib-mediated effects were associated with the induction of tumor suppressor miR-34a and suppression of WNT/?-catenin signaling. Our findings demonstrated that regorafenib treatment was associated with the increased level of miR-34a, resulting in reversing drug resistance and cancer-initiating cell phenotypes by degrading WNT/?-catenin in CRC. CONCLUSION:Regorafenib might be a potential drug for colon cancer stem-like cells and it should be investigated in future clinical trials.

SUBMITTER: Cai MH

PROVIDER: S-EPMC6045878 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling.

Cai Mao-Hua MH Xu Xiao-Gang XG Yan Shi-Li SL Sun Ze Z Ying Yin Y Wang Bai-Kui BK Tu Yue-Xing YX

Journal of experimental & clinical cancer research : CR 20180713 1

<h4>Background</h4>Colorectal cancer (CRC) is one of the most prevalent malignancies in the world and developed drug resistance has represented one of the most challenging tasks for management. The current therapeutic regimens may select and enrich cancer stem-like cells (CSCs) resulting in the increased resistance against treatment, metastatic potential and mortality. Regorafenib is a multi-kinase inhibitor, an FDA-approved last-of-line treatment for patients with chemo-refractory metastatic CR ...[more]

PMID: 30005681

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Project 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 ?-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.

Dataset Information

Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling.

Publications

Regorafenib suppresses colon tumorigenesis and the generation of drug resistant cancer stem-like cells via modulation of miR-34a associated signaling.

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