Targeting the KRAS-p38-ATF4 axis enhances the therapeutic sensitivity of the peptide PDBAG1 in ovarian cancer via stress response modulation

Abstract

We previously screened a peptide PDBAG1 that remarkably inhibited triple-negative breast cancer, and found that its target was C1QBP. Recently, C1QBP has been reported as a potential tumor marker in ovarian cancer, which of the mortality rate ranks first among malignant tumors of the female reproductive tract. However, it is unclear whether and how PDBAG1 plays a regulatory role in ovarian cancer. Here, we first found that PDBAG1 definitely inhibited the growth and metastasis of ovarian cancer in vitro and in vivo. PDBAG1 downregulated the protein level of C1QBP and damaged mitochondria in ovarian cancer. Furthermore, we analyzed the overall impact of PDBAG1 on ovarian cancer cells through transcriptomics, and found that KRAS, inflammation and stress-related signals were dramatically activated. The accuracy of the transcriptome sequencing results was also subsequently verified. Moreover, we combined the inhibitors of the classic downstream MAPK signaling pathway of KRAS and the integrated stress inhibitor with PDBAG1, and found that the p38 MAPK inhibitor, Adezmapimod, significantly enhanced the inhibitory effect of PDBAG1 on ovarian cancer and inhibited the upregulation of the crucial stress response transcription factor ATF4 caused by PDBAG1. Collectively, our research results revealed the function and mechanism of the peptide PDBAG1 in ovarian cancer, providing new insights into clinical drug development for ovarian cancer.