MicroRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by regulating PPP2R1B expression in colorectal cancer
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Updated: Apr 5, 2026
An In Vitro Protocol for Evaluating MicroRNA Levels, Functions, and Associated Target Genes in Tumor Cells
Published on: May 21, 2019
Yang Zhang1, G Talmon2, J Wang3
11] Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, NE 68198, USA [2] Department of Genetics, Cell Biology and Anatomy, 985950 Nebraska Medical Center, Omaha, NE 68198, USA.
Abstract:
Drug resistance is one of the major hurdles for cancer treatment. However, the underlying mechanisms are still largely unknown and therapeutic options remain limited. In this study, we show that microRNA (miR)-587 confers resistance to 5-fluorouracil (5-FU)-induced apoptosis in vitro and reduces the potency of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-587 modulates drug resistance through downregulation of expression of PPP2R1B, a regulatory subunit of the PP2A complex, which negatively regulates AKT activation. Knockdown of PPP2R1B expression increases AKT phosphorylation, which leads to elevated XIAP expression and enhanced 5-FU resistance; whereas rescue of PPP2R1B expression in miR-587-expressing cells decreases AKT phosphorylation/XIAP expression, re-sensitizing colon cancer cells to 5-FU-induced apoptosis. Moreover, a specific and potent AKT inhibitor, MK2206, reverses miR-587-conferred 5-FU resistance. Importantly, studies of colorectal cancer specimens indicate that the expression of miR-587 and PPP2R1B positively and inversely correlates with chemoresistance, respectively, in colorectal cancer. These findings indicate that the miR-587/PPP2R1B/pAKT/XIAP signaling axis has an important role in mediating response to chemotherapy in colorectal cancer. A major implication of our study is that inhibition of miR-587 or restoration of PPP2R1B expression may have significant therapeutic potential to overcome drug resistance in colorectal cancer patients and that the combined use of an AKT inhibitor with 5-FU may increase efficacy in colorectal cancer treatment.
Insights
MicroRNA-587 promotes 5-fluorouracil resistance in colorectal cancer by downregulating PPP2R1B, increasing AKT activation and XIAP expression. Inhibiting miR-587 or restoring PPP2R1B may overcome chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Drug resistance remains a significant challenge in cancer therapy, limiting treatment options.
- The precise mechanisms underlying chemoresistance, particularly to 5-fluorouracil (5-FU), are not fully understood.
- MicroRNAs (miRNAs) are increasingly recognized for their roles in regulating cellular processes, including drug response.
Purpose of the Study:
- To investigate the role of microRNA-587 (miR-587) in mediating resistance to 5-fluorouracil (5-FU) in colorectal cancer.
- To elucidate the molecular mechanisms by which miR-587 influences 5-FU sensitivity.
- To explore the therapeutic potential of targeting the miR-587 pathway for overcoming chemoresistance.
Main Methods:
- In vitro studies using cell lines to assess the effect of miR-587 on 5-FU-induced apoptosis.
- In vivo mouse xenograft models to evaluate 5-FU efficacy in the presence of miR-587.
- Analysis of the miR-587/PPP2R1B/AKT/XIAP signaling axis, including gene expression and protein phosphorylation.
- Correlation studies in colorectal cancer patient specimens.
Main Results:
- miR-587 overexpression conferred resistance to 5-FU in vitro and reduced 5-FU's anti-tumor effect in vivo.
- miR-587 downregulated PPP2R1B expression, leading to increased AKT phosphorylation and XIAP upregulation, thereby enhancing 5-FU resistance.
- Restoring PPP2R1B expression re-sensitized cells to 5-FU, while AKT inhibition reversed miR-587-mediated resistance.
- Clinical specimens showed a positive correlation between miR-587 and chemoresistance, and an inverse correlation between PPP2R1B and chemoresistance.
Conclusions:
- The miR-587/PPP2R1B/pAKT/XIAP axis is a critical mediator of 5-FU response in colorectal cancer.
- Inhibition of miR-587 or restoration of PPP2R1B presents potential therapeutic strategies to overcome chemoresistance.
- Combination therapy with AKT inhibitors and 5-FU may enhance treatment efficacy in colorectal cancer patients.
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