N-Carbamoyl Alanine-Mediated Selective Targeting for CHEK2-Null Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the major causes of cancer-linked mortality worldwide. Selective therapeutic approaches toward cancer are the need of the hour to combat cancer. Synthetic lethality is a pragmatic targeted cancer therapy in which cancer cell-specific vulnerabilities such as genetic defects/somatic mutations are exploited for selective cancer therapy by targeting genetic interactors (synthetic lethal interactors) of such mutation/defects present in cancer cells. In this study, we investigated the synthetic lethal interaction between checkpoint kinase 2 (CHEK2) and peroxiredoxin-2 (PRDX2) in CRC cells to precisely target CRC cells having CHEK2 defects. We have performed siRNA-mediated silencing and n-carbamoyl alanine (NCA)-mediated inhibition of PRDX2 in CHEK2-null HCT116 cells to confirm the synthetic lethal (SL) interaction between PRDX2 and CHEK2 as the cell population reduced significantly after silencing/inhibition of PRDX2. Additionally, treatment with NCA resulted in an increased level of total ROS in both cell types (HCT116 and CHEK2-null HCT116 cells), which further confirms that inhibition of PRDX2 results in an increased ROS level, which are mainly responsible for DNA double-strand breaks (DSBs). ROS-induced DNA DSBs get repaired in HCT116 cells, in which CHEK2 is in the normal functional state, but these DNA DSBs persist in CHEK2-null HCT116 cells as confirmed by the immunofluorescence analysis of 53BP1 and γ-H₂AX. Finally, CHEK2-null HCT116 cells undergo apoptosis due to persistent DNA damage as confirmed by immunofluorescence analysis of cleaved caspase-3. The findings of this study suggest that PRDX2 has a SL interaction with CHEK2, and this interaction can be exploited for the targeted cancer therapy using NCA as a drug inhibitor of PRDX2 for the therapy of colorectal cancer having CHEK2 defects. Further studies are warranted to confirm the interaction in the preclinical model.

SUBMITTER: Ahmad A 

PROVIDER: S-EPMC9026038 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature