In vivo detection of dysregulated choline metabolism in paclitaxel-resistant ovarian cancers with proton magnetic resonance spectroscopy

Abstract

Background Chemoresistance gradually develops during treatment of epithelial ovarian cancer (EOC). Metabolic alterations, especially in vivo easily detectable metabolites in paclitaxel (PTX)-resistant EOC remain unclear. Methods Xenograft models of the PTX-sensitive and PTX-resistant EOCs were built. Using a combination of in vivo proton-magnetic resonance spectroscopy (1H-MRS), metabolomics and proteomics, we investigated the in vivo metabolites and dysregulated metabolic pathways in the PTX-resistant EOC. Furthermore, we analyzed the RNA expression to validate the key enzymes in the dysregulated metabolic pathway. Results On in vivo 1H-MRS, the ratio of (glycerophosphocholine + phosphocholine) to (creatine + phosphocreatine) ((GPC + PC) to (Cr + PCr))(i.e. Cho/Cr) in the PTX-resistant tumors (1.64 [0.69, 4.18]) was significantly higher than that in the PTX-sensitive tumors (0.33 [0.10, 1.13]) (P = 0.04). Forty-five ex vivo metabolites were identified to be significantly different between the PTX-sensitive and PTX-resistant tumors, with the majority involved of lipids and lipid-like molecules. Spearman’s correlation coefficient analysis indicated in vivo and ex vivo metabolic characteristics were highly consistent, exhibiting the highest positive correlation between in vivo GPC + PC and ex vivo GPC (r = 0.885, P < 0.001). These metabolic data suggested that abnormal choline concentrations were the results from the dysregulated glycerophospholipid metabolism, especially choline metabolism. The proteomics data indicated that the expressions of key enzymes glycerophosphocholine phosphodiesterase 1 (GPCPD1) and glycerophosphodiester phosphodiesterase 1 (GDE1) were significantly lower in the PTX-resistant tumors compared to the PTX-sensitive tumors (both P < 0.01). Decreased expressions of GPCPD1 and GDE1 in choline metabolism led to an increased GPC levels in the PTX-resistant EOCs, which was observed as an elevated total choline (tCho) on in vivo 1H-MRS. Conclusions These findings suggested that dysregulated choline metabolism was associated with PTX-resistance in EOCs and the elevated tCho on in vivo 1H-MRS could be as an indicator for the PTX-resistance in EOCs.

Single-Cell RNA Sequencing Reveals the Role of Epithelial Cell Marker Genes in Predicting the Prognosis of Colorectal Cancer Patients

“…LGALS2 reportedly inhibits the development of CRC and lymph node metastasis of gastric cancer [50,51]. GDE1 expression is significantly reduced in drugresistant ovarian cancer samples [52]. Consistent with these findings, our results suggested that high expression of LGALS2 and GDE1 in CRC patients implies a good prognosis.…”

A Treg‐related riskscore model may improve the prognosis evaluation of colorectal cancer

“…As far as the genes in riskscore model are concerned, we have found that GDE1, GSR, TAMM41 and TIGD6 are favorable prognostic genes, while HSPB1, AOC2, and TBX19 are risk genes. Glycerophosphodiester phosphodiesterase 1 (GDE1) has been identified as a key enzyme associated with paclitaxel resistance in ovarian cancer 16 . Decreased expressions of GDE1 choline metabolism could elevate glycerophosphocholine levels in the paclitaxel‐resistant epithelial ovarian cancer 16 .…”

Metabolic reprogramming of the tumor immune microenvironment in ovarian cancer: A novel orientation for immunotherapy

“…Not only does metabolic adaptation of tumors take place throughout the course of OC, but it also happens during the course of therapy, which results in drug resistance (134)(135)(136)(137). Metabolic reprogramming of the TIME in ovarian cancer leads to chemoresistance.…”

“…Moreover, paclitaxel resistance in ovarian cancer is associated with choline metabolism reprogramming. The expression of glycerophosphocholine phosphodiesterase 1 and glycerophosphodiester phosphodiesterase 1 in EOC was discovered to be elevated using proton magnetic resonance spectroscopy, and total choline was found to be elevated (136). Owing to the cunning metabolic adaptations of OC, monotherapy is frequently ineffective.…”