title: Phospholipase D1 and choline kinase-α are interactive targets in breast cancer.
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.
authors.affiliation: 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.
authors.forename: Mayur
authors.initials: M
authors.lastname: Gadiya
authors.affiliation: 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.
authors.forename: Noriko
authors.initials: N
authors.lastname: Mori
authors.affiliation: Department of Circulation and Medical Imaging; Norwegian University of Science and Technology (NTNU); Trondheim, Norway.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Mironchik
authors.affiliation: 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.
authors.forename: Samata
authors.initials: S
authors.lastname: Kakkad
authors.affiliation: Department of Circulation and Medical Imaging; Norwegian University of Science and Technology (NTNU); Trondheim, Norway.
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Gribbestad
authors.affiliation: 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.
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
authors.affiliation: 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.
authors.forename: Balaji
authors.initials: B
authors.lastname: Krishnamachary
authors.affiliation: 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.
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002797:Choline Kinase / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010713:Phosphatidylcholines / Q000378:metabolism; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D010713:Phosphatidylcholines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C011246:essential 303 forte; C517212:CHKA protein, human; D002797:Choline Kinase; D010739:Phospholipase D; C106801:phospholipase D1
keywords: RNA interference; breast cancer; choline kinase-alpha; magnetic resonance spectroscopy; phospholipase D1