RESUMO
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.
Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Mutação , Linhagem Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , DNA Helicases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genéticaRESUMO
BRG1 is one of two catalytic subunits of the SWI/SNF ATP-dependent chromatin-remodeling complex. In cancer, it has been hypothesized that BRG1 acts as a tumor suppressor. Further study has shown that, under certain circumstances, BRG1 acts as an oncogene. Targeted knockout of BRG1 has proven successful in most cancers in suppressing tumor growth and proliferation. Furthermore, BRG1 effects cancer proliferation in oncogenic KRAS mutated cancers, with varying directionality. Thus, dissecting BRG1's interaction with various cellular pathways can highlight possible intermediates that can facilitate the design of different treatment methods, including BRG1 inhibition. Autophagy and apoptosis are two important cellular responses to stress. BRG1 plays a direct role in autophagy and apoptosis and likely promotes autophagy and suppresses apoptosis, supporting unfettered cancer growth. PRMT5 inhibits transcription by interacting with ATP-dependent chromatin remodeling complexes, such as SWI/SNF. When PRMT5 associates with the SWI/SNF complex, including BRG1, it represses tumor suppressor genes. The Ras/Raf/MAPK/ERK1/2 pathway in cancers is a signal transduction pathway involved in the transcription of genes related to cancer survival. BRG1 has been shown to effect KRAS-driven cancer growth. BRG1 associates with several proteins within the signal transduction pathway. In this review, we analyze BRG1 as a promising target for cancer inhibition and possible synergy with other cancer treatments.