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Sulindac Sulfide Suppresses Oncogenic Transformation Through let-7b-Mediated Repression of K-Ras Signaling
Abstract:
Cell transformation is a key early event in tumorigenesis, yet the molecular mechanisms underlying its chemoprevention remain poorly defined. Here, we show that sulindac sulfide (SS), the active metabolite of the NSAID sulindac, inhibits chemically induced transformation of NIH/3T3 cells through a COX-independent mechanism. SS treatment upregulates the tumor-suppressive microRNA let-7b, which directly targets K-Ras and suppresses downstream ERK signaling. Notably, K-Ras negatively regulates let-7b via activation of ERK and LIN28B, forming a reciprocal feedback loop that drives transformation. SS disrupts this loop by downregulating p-ERK and LIN28B, thereby restoring let-7b expression. Functional analyses confirmed that let-7b, but not let-7g, is required for SS-mediated inhibition of transformation. In human colon cancer tissues and cell lines, let-7b is downregulated, but restored upon SS treatment. These findings identify a novel let-7b/K-Ras/LIN28B/ERK regulatory axis targeted by SS and provide mechanistic insight into its role in early-stage cancer chemoprevention.
Insights
Sulindac sulfide inhibits cell transformation by upregulating the tumor-suppressive microRNA let-7b. This mechanism targets a K-Ras/LIN28B/ERK feedback loop, offering insights into early cancer chemoprevention.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cell transformation is a critical step in cancer development.
- Understanding chemoprevention mechanisms is vital for early cancer intervention.
- The role of microRNAs in tumorigenesis and drug action is an active research area.
Purpose of the Study:
- To elucidate the molecular mechanisms by which sulindac sulfide (SS) prevents chemically induced cell transformation.
- To investigate the involvement of microRNAs, specifically let-7b, in SS-mediated chemoprevention.
- To identify the regulatory pathways targeted by SS in cancer cells.
Main Methods:
- Utilized NIH/3T3 cell transformation assays.
- Assessed the effect of sulindac sulfide on microRNA and protein expression levels.
- Investigated the let-7b/K-Ras/LIN28B/ERK regulatory axis.
- Analyzed human colon cancer tissues and cell lines.
Main Results:
- Sulindac sulfide (SS) inhibited cell transformation via a COX-independent pathway.
- SS treatment upregulated tumor-suppressive microRNA let-7b, which targets K-Ras.
- A feedback loop involving K-Ras, ERK, and LIN28B driving transformation was identified and disrupted by SS.
- let-7b, but not let-7g, was essential for SS's inhibitory effect on transformation.
- let-7b was downregulated in human colon cancer and restored by SS treatment.
Conclusions:
- Sulindac sulfide disrupts a novel let-7b/K-Ras/LIN28B/ERK regulatory axis.
- This disruption leads to the restoration of let-7b expression and inhibition of cell transformation.
- The findings provide mechanistic insight into the chemopreventive effects of SS in early-stage cancer.
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