Prostaglandin F2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F2α-dependent and F2α-independent mechanism

Abstract

Background: Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F_2α synthase (PGF_2α) (PGFS), an enzyme that catalyzes the production of PGF_2α, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear.

Aim: To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.

Methods: The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products.

Results: Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment in vitro and in vivo. The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF_2α reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF_2α-independent manner. PGF_2α exerts its protective effect against DNA damage by reducing ROS levels.

Conclusion: PGFS promotes resistance to Oxa in CRC via both PGF_2α-dependent and PGF_2α-independent mechanisms.

Keywords: Colorectal cancer; DNA damage; Drug resistance; Oxaliplatin; Prostaglandin F2αsynthase.