ROS-Induced DCTPP1 Upregulation Contributes to Cisplatin Resistance in Ovarian Cancer

Abstract

Cisplatin resistance hinders the improvement of the prognosis of patients with ovarian cancer. Cisplatin induces cancer cell apoptosis by inducing reactive oxygen species (ROS). dCTP pyrophosphatase 1 (DCTPP1) is a newly discovered dNTP pyrophosphatase. This study aimed to identify the role of DCTPP1 in oxidative stress and cisplatin response of ovarian cancer. Our results indicates cisplatin-induced ROS generation was responsible for the upregulation of DCTPP1 in ovarian cancer cells, whereas DCTPP1 knockdown significantly enhanced the sensitivity of ovarian cancer cells to cisplatin, reflect in reactive oxygen species (ROS) generation, double-strand DNA breaks, and cell apoptosis. The expression of redox-related genes and the activation of the PI3/Akt signaling pathway were also inhibited by DCTPP1 knockdown. Our data proposes that the development of therapeutic approaches targeting DCTPP1 may be useful in the treatment of ovarian cancer.

Expression of human dCTP pyrophosphatase 1 (DCTPP1) and its association with cisplatin resistance characteristics in ovarian cancer

“…The GEPIA2 online analysis tool found that the DCTPP1 mRNA expression level in OC tissue was significantly higher than that in normal ovarian tissue (p < 0.05) (Figure 1A), which is consistent with our previous work. 15 As shown in Figure 1B,C, time-dependent ROC curves by Sangerbox online analysis tool show that higher expression levels of DCTPP1 mRNA were significantly correlated with shorter OS (log-rank p = 0.028) and DFS (log-rank p = 0.02). We use the standard metric of Area Under the Curve (AUC) of an ROC curve as the comparison metric, the best AUC of the ROC curve for OS and DFS was 0.55 (95% CI, 0.48-0.63) and 0.56 (95% CI, 0.48-0.63).…”

“…ROS in OC cells, increasing their sensitivity to cisplatin treatment. 15 Therefore, in this study, we examined the accumulation of ROS in SKOV3/S cells and SKOV3/DDP cells after cisplatin treatment.…”

“…7,8,10,11 The DCTPP1 gene is a new member of the NTP-PPase family and has been predicted as a potential target for antitumour drug development. [12][13][14][15] DCTPP1 locates on chromosome 16 and encodes a dCTP (deoxycytidine triphosphate) pyrophosphatase. 16 DCTPP1 gene is highly expressed in the cell nucleus and is involved in maintaining the balance of dCTP levels within the nucleus.…”

Construction and Validation of a Prognostic Model Based on mRNAsi-Related Genes in Breast Cancer

“…Similarly, HMGB3 is also a prototypical marker of breast cancer progression but worsens cancer progression primarily by promoting formation of breast layers of breast cancer cells [ 40 , 41 ]. DCTPP1 is an oncogene regulated by the oncogenic factor miR-378a-3p, and this gene facilitates breast cancer cell proliferation through the interference of DNA repair signaling pathway [ 42 , 43 ]. The phenomenon of overexpression of SHCBP1 in breast cancer has been studied, and cellular experiments have demonstrated that this gene directly regulates breast cancer cell proliferation and promotes the cell cycle [ 44 ].…”

ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance

“…The increase in intracellular ROS levels in OC has been shown to contribute to therapeutic resistance. For instance, an increase in ROS in OC results in the overexpression of dCTP pyrophosphatase I (DCTPP1), which has a role in DNA damage repair and plays a major contribution to cisplatin resistance [ 181 ]. By a differing mechanism, the upregulation of calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) in response to increasing levels of ROS reprograms the cellular redox system through the phosphorylation of inositol triphosphate3-kinase B (ITPKB), resulting in adaptive redox homeostasis and increased resistance to cisplatin treatment [ 182 ].…”