新規抗がん剤候補化合物ACAGT-007aによる細胞死誘導におけるDNA損傷応答タンパク質BRAT1の役割

抄録

We have previously identified an anti-cancer compound ACA-28 and its lead compound ACAGT-007a (GT-7) as novel regulators of ERK MAPK signaling using our chemical genetic screen. ACA-28 and GT-7 have unique properties to suppress cell proliferation and induce cell death by further activating ERK in cancer cells with high ERK activity, such as melanoma and pancreatic cancer cells. However, the detailed mechanism of cell death induction by these compounds has not been elucidated. To determine protein targets of ACA-28 relevant for apoptosis induction, we searched for molecules that can bind to ACA-28 and found that BRCA1-associated ATM activator1 (BRAT1), which acts as a DNA damage response protein (DDR protein) upon DNA damage, is a candidate binding protein for ACA-28. We also established a melanoma cell line with acquired resistance to GT-7 (referred to as ACA-R-SK). Interestingly, the expression levels of BRAT1 were significantly higher in ACA-R-SK cells as compared with the original SK-MEL-28 cells. Furthermore, the addition of GT-7 markedly decreased the expression of BRAT1 in both cell lines. Knockdown of BRAT1 by introducing BRAT1 siRNA into the ACA-28 resistant ACA-R-SK cells enhanced cell death induction by GT-7. These results suggest that the down-regulation of BRAT1 may play a key role in the mechanism of cell death induction by GT-7. In this presentation, I will discuss the possible mechanisms of BRAT1 downregulation by GT-7 and the role of BRAT1 in the induction of cell death by GT-7.

References

1) Satoh et al. Identification of ACA-28, a 1’ -acetoxychavicol acetate analogue compound, as a novel modulator of ERK MAPK signaling, which preferentially kills human melanoma cells. Genes Cells 2017, 22, 608-618

2) Khandakar et al. ACAGT-007a, an ERK MAPK Signaling Modulator, in Combination with AKT Signaling Inhibition Induces Apoptosis in KRAS Mutant Pancreatic Cancer T3M4 and MIA-Pa-Ca-2 Cells. Cells 2022,11,702