Phospholipase D1 and choline kinase-α are interactive targets in breast cancer

Mayur Gadiya Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USA

Noriko Mori Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USA

Maria D Cao Department of Circulation and Medical Imaging; Norwegian University of Science and Technology (NTNU); Trondheim, Norway

Yelena Mironchik Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USA

Samata Kakkad Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USA

Ingrid S Gribbestad Department of Circulation and Medical Imaging; Norwegian University of Science and Technology (NTNU); Trondheim, Norway

Kristine Glunde Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USA; Sidney Kimmel Comprehensive Cancer Center; The Johns Hopkins University School of Medicine; Baltimore, MD USA

Balaji Krishnamachary Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USACorrespondence[email protected] [email protected]

Zaver M Bhujwalla Division of Cancer Imaging Research; The Johns Hopkins University In Vivo Cellular and Molecular Imaging Center; Russell H. Morgan Department of Radiology and Radiological Science; The Johns Hopkins University School of Medicine; Baltimore, MD USA; Sidney Kimmel Comprehensive Cancer Center; The Johns Hopkins University School of Medicine; Baltimore, MD USACorrespondence[email protected] [email protected]

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Abstract

A consistent metabolic hallmark observed in multiple cancers is the increase of cellular phosphocholine (PC) and total choline-containing compounds (tCho), which is closely related to malignant transformation, invasion, and metastasis. Enzymes in choline phospholipid metabolism present attractive targets to exploit for treatment, but require a clear understanding of the mechanisms underlying the altered choline phospholipid metabolism observed in cancer. Choline kinase-α (Chk-α) is an enzyme in the Kennedy pathway that phosphorylates free choline (Cho) to PC, and its upregulation in several cancers is a major contributor to increased PC levels. Similarly, increased expression and activity of phospholipase D1 (PLD1), which converts phosphatidylcholine (PtdCho) to phosphatidic acid (PA) and Cho, has been well documented in gastric, ovarian and breast cancer. Here we report a strong correlation between expression of Chk-α and PLD1 with breast cancer malignancy. Data from patient samples established an association between estrogen receptor (ER) status and Chk-α and PLD1 expression. In addition, these two enzymes were found to be interactive. Downregulation of Chk-α with siRNA increased PLD1 expression, and downregulation of PLD1 increased Chk-α expression. Simultaneous silencing of PLD1 and Chk-α in MDA-MB-231 cells increased apoptosis as detected by the TUNEL assay. These data provide new insights into choline phospholipid metabolism of breast cancer, and support multiple targeting of enzymes in choline phospholipid metabolism as a strategy for treatment.

Keywords: :

10.4161/cbt.28165

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This work was supported by NIH R01CA136576, R01CA138515, R01CA73850, R01CA82337, P50CA103175, P30CA006973, and R01 CA134695. We thank Ms Flonne Wildes for expert technical assistance and Dr Franca Podo for useful discussions.

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Phospholipase D1 and choline kinase-α are interactive targets in breast cancer

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Phospholipase D1 and choline kinase-α are interactive targets in breast cancer

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