Abstract
Metabolic reprogramming could promote cellular adaptation in response to chemotherapeutic drugs in cancer cells. Herein, we aimed to characterize the metabolomic profiles regulated by Dipeptidyl Peptidase 4 (DPP4) in methotrexate (MTX)-resistant gestational trophoblastic neoplastic (GTN) cells. A total of eighty metabolites were found to be commonly altered in DPP4-depleted JAR/MTX and JEG3/MTX cells. Cholesterol biosynthesis-related metabolites were markedly impacted by DPP4 knockdown in MTX-resistant sublines. Manipulation of DPP4 expression remarkably affected the level of cellular cholesterol in GTN cells. Our analysis also identified 24-Dehydrocholesterol Reductase (DHCR24) as a potential downstream effector of DPP4. Manipulation of DHCR24 expression affected cellular cholesterol level, reactive oxygen species (ROS) accumulation, and chemosensitivity to MTX in GTN cell models. In addition, over-expression of DHCR24 could markedly restore cellular cholesterol level and rescue cell survival in DPP4-depleted MTX-resistant GTN cells. Highly correlated expression of DPP4 and DHCR24 was observed in clinical GTN specimens. Further, DPP4 inhibitor sitagliptin effectively inhibited cholesterol biosynthesis, reduced DHCR24 expression and enhanced MTX-induced cytotoxicity in vitro and in vivo. In conclusion, our findings suggested that DPP4 might regulate DHCR24-mediated cholesterol biosynthesis to promote methotrexate resistance in GTN cells. Targeting DPP4/DHCR24 signaling might help to sensitize MTX-resistant GTN to MTX treatment.
Highlights
Gestational trophoblastic neoplasia (GTN), including epithelioid trophoblastic tumor, placental site trophoblastic tumor, choriocarcinoma, and invasive mole, is one of the curable cancers due to its intrinsic sensitivity to chemotherapeutic drugs [1]
The level of the metabolites involved in steroid/cholesterol biosynthesis (Squalene, Cholesterol, and 7-dehydrocholesterol) was reduced in shDPP4 group compared to Scr control in JAR/MTX and JEG3/MTX cells (Figure 1D)
Dipeptidyl Peptidase 4 (DPP4) has been proposed as a new adipokine, which might play an important role in lipid metabolism in adipose tissues [39]
Summary
Gestational trophoblastic neoplasia (GTN), including epithelioid trophoblastic tumor, placental site trophoblastic tumor, choriocarcinoma, and invasive mole, is one of the curable cancers due to its intrinsic sensitivity to chemotherapeutic drugs [1]. A number of genes have been potentially implicated in the development of MTX resistance in GTN, including dihydrofolate reductase (DHFR) [5], ATPbinding-cassette (ABC) transporter MRP1 [6], CD105 [7], Type I interferons [8], and SLAMF1 [9]. Activation of cholesterol biosynthesis pathway has been shown to contribute to the development of chemoresistance in cancer cells by maintaining lipid rafts [11], ABC transporter activity [12], reactive oxygen species (ROS) homeostasis [13,14,15], and mitochondrial integrity [16]. Some cholesterol synthases (CYP51A1, HMGCR, HMGCS1, etc.) have been shown to regulate drug resistance in various cancers. Cholesterol biosynthesis inhibitors including Statins and Bisphosphonates could sensitize cancer cells to anticancer drugs [20]. The role of cholesterol biosynthesis pathway in the development of MTX resistance in GTN still remains largely unknown
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