Molecular mechanism of resistance to the anticancer drug ACP52C in the A549 cell line

Abstract

The transcription factor CP2c plays an important role as an oncogene and controls cell proliferation, cell cycle, and differentiation. We previously identified that a CP2c-targeting peptide derivative led to apoptotic cell death of cancer cell lines of various origins when it was linked to the cell-penetrating peptide iRGD, with no adverse effect on normal cells. We called this peptide derivative ACP52C (anti-cancer peptide 52C). Importantly, compared to most cancer cell lines, the non-small cell lung cancer (NSCLC) cell lines were resistant to the anticancer effect of ACP52C. In this study, I found that NSCLC cells, compared to other cancer cell types, express murine double minute 2 (MDM2) protein at low levels of its 90 kDa isoform (p90) and high levels of its 60 kDa isoform (p60). I confirmed that high levels of MDM2 p60 in NSCLC were caused by caspase 2-mediated protein cleavage but not by alternative splicing or the SNP mutantion, consistent with the previous reports. Conditional overexpression of MDM2 p90 or treatment with a caspase 2 inhibitor could overcome the resistance to ACP52C leading to the cell death. Therefore, these results suggest that ACP52C resistance in NSCLC is caused by a tilted balance between MDM2 p60 and p90 levels and could be overcome by inhibiting the caspase 2 activity.