TY - JOUR
T1 - Phospholipase D1 and choline kinase-α are interactive targets in breast cancer
AU - Gadiya, Mayur
AU - Mori, Noriko
AU - Cao, Maria D.
AU - Mironchik, Yelena
AU - Kakkad, Samata
AU - Gribbestad, Ingrid S.
AU - Glunde, Kristine
AU - Krishnamachary, Balaji
AU - Bhujwalla, Zaver M.
N1 - Funding Information:
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.
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Choline kinase-alpha
KW - Magnetic resonance spectroscopy
KW - Phospholipase D1
KW - RNA interference
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U2 - 10.4161/cbt.28165
DO - 10.4161/cbt.28165
M3 - Article
C2 - 24556997
AN - SCOPUS:84899860775
SN - 1538-4047
VL - 15
SP - 593
EP - 601
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 5
ER -