Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China.
Liver Unit, University of Calgary, Calgary T1W0K6, Canada.
World J Gastroenterol. 2023 Oct 21;29(39):5452-5470. doi: 10.3748/wjg.v29.i39.5452.
Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F synthase (PGF) (PGFS), an enzyme that catalyzes the production of PGF, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear.
To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.
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.
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 and . The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF-independent manner. PGF exerts its protective effect against DNA damage by reducing ROS levels.
PGFS promotes resistance to Oxa in CRC both PGF-dependent and PGF-independent mechanisms.
奥沙利铂（Oxa）是结直肠癌（CRC）的一线化疗药物，而 Oxa 耐药性是治疗失败的关键。前列腺素 F 合酶（PGFS）（PGFS）是一种催化 PGF 生成的酶，参与多种肿瘤的增殖和生长。然而，PGFS 在 CRC 中奥沙利铂耐药性中的作用尚不清楚。
探讨 PGFS 在介导 CRC 奥沙利铂耐药中的作用及相关机制。
采用实时荧光定量 PCR 和 Western blot 检测 37 对 CRC 组织及其癌旁组织中 PGFS 的 mRNA 和蛋白表达水平。在获得奥沙利铂耐药性的 CRC 细胞系（HCT116-OxR 和 HCT8-OxR）及其亲本细胞系（HCT116 和 HCT8）中转染 PGFS 过表达或敲低载体，评估其对细胞增殖、化疗耐药性、凋亡和 DNA 损伤的影响。为了确定潜在的机制，在存在 PGFS 抑制剂或其产物的情况下，检测 CRC 细胞中铂-DNA 加合物和活性氧（ROS）水平。
与相邻正常组织相比，37 例 CRC 组织中 PGFS 的蛋白和 mRNA 水平均升高。奥沙利铂以剂量依赖性方式诱导亲本 HCT116 和 HCT8 细胞中 PGFS 的表达。此外，在亲本 CRC 细胞中过表达 PGFS 可显著减轻奥沙利铂诱导的增殖抑制、凋亡和 DNA 损伤。相反，在奥沙利铂耐药的 HCT116 和 HCT8 细胞（HCT116-OxR 和 HCT8-OxR）中敲低 PGFS 可增强奥沙利铂处理的作用。PGFS 抑制剂吲哚美辛的添加增强了奥沙利铂引起的细胞毒性。PGFS 催化产物 PGF 的处理逆转了 PGFS 敲低对奥沙利铂敏感性的影响。有趣的是，PGFS 以 PGF 非依赖性方式抑制铂-DNA 加合物的形成。PGF 通过降低 ROS 水平发挥其对 DNA 损伤的保护作用。
PGFS 通过 PGF 依赖和非依赖机制促进 CRC 对奥沙利铂的耐药性。
