Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer model<i>in vivo</i>as monitored by<sup>31</sup>P MRS

Wijnen, Jannie P.; Jiang, Lu; Greenwood, Tiffany R.; Cheng, Maojie; Döpkens, Mailin; Cao, Maria Dung; Bhujwalla, Zaver M.; Krishnamachary, Balaji; Klomp, Dennis W. J.; Glunde, Kristine

doi:10.1002/nbm.3106

Cited by 13 publications

(17 citation statements)

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“…We have investigated the effects of targeting two glycerophosphodiesterase genes, GDPD5 and GDPD6, which have been shown to be involved in the regulation of choline phospholipid metabolism in breast cancer, in particular the degradation of GPC to free choline and glycerol‐3‐phosphate . Silencing of GDPD5 and GDPD6 in breast cancer cells increased the GPC levels, which further supports their roles as GPC‐specific regulators in breast cancer.…”

Section: Discussionmentioning

confidence: 71%

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion

et al. 2016

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Abnormal choline phospholipid metabolism is associated with oncogenesis and tumor progression. We have investigated the effects of targeting choline phospholipid metabolism by silencing two glycerophosphodiesterase genes, GDPD5 and GDPD6, using small interfering RNA (siRNA) in two breast cancer cell lines, MCF-7 and MDA-MB-231. Treatment with GDPD5 and GDPD6 siRNA resulted in significant increases in glycerophosphocholine (GPC) levels, and no change in the levels of phosphocholine (PC) and free choline, which further supports their role as GPC specific regulators in breast cancer. The GPC levels were more than twofold increased during GDPD6 silencing, and marginally increased during GDPD5 silencing. DNA laddering was negative in both cell lines treated with GDPD5 and GDPD6 siRNA, indicating absence of apoptosis. Treatment with GDPD5 siRNA caused a decrease in cell proliferation in both breast cancer cell lines at 72h, while GDPD6 siRNA treatment decreased cell proliferation in MCF-7 at 72h, but not in MDA-MB-231 cells. Decreased cell migration and invasion were observed in MDA-MB-231 cells treated with GDPD5 or GDPD6 siRNA, where a more pronounced reduction in cell migration and invasion was observed under GDPD5 siRNA treatment as compared to GDPD6 siRNA treatment. In conclusion, GDPD6 silencing increased the GPC levels in breast cancer cells more profoundly than GDPD5 silencing, while the effects of GDPD5 silencing on cell proliferation, migration, and invasion were more severe than those of GDPD6 silencing. Our results suggest that silencing GDPD5 and GDPD6 alone or in combination may have potential as new molecular targeting strategy for breast cancer treatment.

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Section: Discussionmentioning

confidence: 71%

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion

et al. 2016

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“…Phosphorus MRS measurements of MDA-MB-231 breast cancer xenografts with constitutively silenced GDPD5 in nude mice also displayed an increase in GPC (164). GDPD5 expression was found to correlate with breast cancer malignancy (165).…”

Section: Glycerophosphodiesterasesmentioning

confidence: 95%

Targeting Phospholipid Metabolism in Cancer

2016

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All cancers tested so far display abnormal choline and ethanolamine phospholipid metabolism, which has been detected with numerous magnetic resonance spectroscopy (MRS) approaches in cells, animal models of cancer, as well as the tumors of cancer patients. Since the discovery of this metabolic hallmark of cancer, many studies have been performed to elucidate the molecular origins of deregulated choline metabolism, to identify targets for cancer treatment, and to develop MRS approaches that detect choline and ethanolamine compounds for clinical use in diagnosis and treatment monitoring. Several enzymes in choline, and recently also ethanolamine, phospholipid metabolism have been identified, and their evaluation has shown that they are involved in carcinogenesis and tumor progression. Several already established enzymes as well as a number of emerging enzymes in phospholipid metabolism can be used as treatment targets for anticancer therapy, either alone or in combination with other chemotherapeutic approaches. This review summarizes the current knowledge of established and relatively novel targets in phospholipid metabolism of cancer, covering choline kinase α, phosphatidylcholine-specific phospholipase D1, phosphatidylcholine-specific phospholipase C, sphingomyelinases, choline transporters, glycerophosphodiesterases, phosphatidylethanolamine N-methyltransferase, and ethanolamine kinase. These enzymes are discussed in terms of their roles in oncogenic transformation, tumor progression, and crucial cancer cell properties such as fast proliferation, migration, and invasion. Their potential as treatment targets are evaluated based on the current literature.

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“…GDPD5 (GDE2) has also emerged as a prognostic marker for neuroblastoma . Increased GPC levels were observed in a 31 P MRS study of triple‐negative MDA‐MB‐231 breast cancer xenograft models in which GDPD5 (GDE2) was constitutively silenced, and which were grown orthotopically in athymic nude mice . Expression levels of GDPD5 (GDE2) were reported to positively correlate with breast cancer malignancy .…”

Section: The Gpc Breakdown Pathway In Cancermentioning

confidence: 99%

Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer

et al. 2019

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Activated choline metabolism is a hallmark of carcinogenesis and tumor progression, which leads to elevated levels of phosphocholine and glycerophosphocholine in all types of cancer tested so far. Magnetic resonance spectroscopy applications have played a key role in detecting these elevated choline phospholipid metabolites. To date, the majority of cancer‐related studies have focused on phosphocholine and the Kennedy pathway, which constitutes the biosynthesis pathway for membrane phosphatidylcholine. Fewer and more recent studies have reported on the importance of glycerophosphocholine in cancer. In this review article, we summarize the recent literature on glycerophosphocholine metabolism with respect to its cancer biology and its detection by magnetic resonance spectroscopy applications.

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Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer modelin vivoas monitored by³¹P MRS

Cited by 13 publications

References 50 publications

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion

Targeting Phospholipid Metabolism in Cancer

Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer

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Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer modelin vivoas monitored by31P MRS

Cited by 13 publications

References 50 publications

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion

Targeting Phospholipid Metabolism in Cancer

Focus on the glycerophosphocholine pathway in choline phospholipid metabolism of cancer

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Product

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Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer modelin vivoas monitored by³¹P MRS