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Impact of carbamazepine on SMARCA4 (BRG1) expression in colorectal cancer: modulation by KRAS mutation status
Aaron Shaykevich1, Danbee Chae1, Isaac Silverman1
1Department of Biology, Yeshiva University, New York, NY, 10033, USA.
Abstract:
SMARCA4 is a gene traditionally considered a tumor suppressor. Recent research has however found that SMARCA4 likely promotes cancer growth and is a good target for cancer treatment. The drug carbamazepine, an autophagy inducer, was used on colorectal cancer cell lines, HCT1116 and Hke3 (KRAS mutant and wildtype). Our study finds that Carbamazepine affects SMARCA4 levels and that this effect is different depending on the KRAS mutation status. This study analyzes the effect of carbamazepine on early-stage autophagy via ULK1 as well as simulates the docking of carbamazepine on KRAS, depending on the mutation status. Our study highlights the therapeutic uses of carbamazepine on cancer, and we propose that carbamazepine in conjunction with other chemotherapies may prove useful in targeting KRAS-mutated colorectal cancer.
Insights
Carbamazepine impacts SMARCA4 levels differently in colorectal cancer cells based on KRAS mutation status. This suggests carbamazepine may be a novel therapeutic for KRAS-mutated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- SMARCA4, traditionally a tumor suppressor, is now recognized for promoting cancer growth and serving as a therapeutic target.
- Colorectal cancer (CRC) presents diverse genetic profiles, notably KRAS mutations, influencing treatment response.
Purpose of the Study:
- To investigate the effect of carbamazepine, an autophagy inducer, on SMARCA4 expression in colorectal cancer cell lines with differing KRAS mutation statuses.
- To explore the mechanism of carbamazepine's action on early-stage autophagy and its interaction with KRAS variants.
Main Methods:
- Treatment of HCT1116 (KRAS mutant) and Hke3 (KRAS wildtype) colorectal cancer cell lines with carbamazepine.
- Analysis of SMARCA4 expression levels post-treatment.
- Assessment of early-stage autophagy markers, including ULK1.
- Molecular docking simulations of carbamazepine with KRAS proteins (mutant and wildtype).
Main Results:
- Carbamazepine significantly altered SMARCA4 levels in a manner dependent on KRAS mutation status.
- The drug's effect on early-stage autophagy (ULK1) was characterized.
- Docking simulations provided insights into carbamazepine's potential interaction with KRAS, varying by mutation.
Conclusions:
- Carbamazepine demonstrates a differential impact on SMARCA4, suggesting a role in modulating cancer cell behavior.
- The findings support carbamazepine's potential as a therapeutic agent, particularly in combination therapies for KRAS-mutated colorectal cancer.
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