title: Pyruvate Carboxylase Is Up-Regulated in Breast Cancer and Essential to Support Growth and Invasion of MDA-MB-231 Cells.
abstract: Pyruvate carboxylase (PC) is an anaplerotic enzyme that catalyzes the carboxylation of pyruvate to oxaloacetate, which is crucial for replenishing tricarboxylic acid cycle intermediates when they are used for biosynthetic purposes. We examined the expression of PC by immunohistochemistry of paraffin-embedded breast tissue sections of 57 breast cancer patients with different stages of cancer progression. PC was expressed in the cancerous areas of breast tissue at higher levels than in the non-cancerous areas. We also found statistical association between the levels of PC expression and tumor size and tumor stage (P < 0.05). The involvement of PC with these two parameters was further studied in four breast cancer cell lines with different metastatic potentials; i.e., MCF-7, SKBR3 (low metastasis), MDA-MB-435 (moderate metastasis) and MDA-MB-231 (high metastasis). The abundance of both PC mRNA and protein in MDA-MB-231 and MDA-MB-435 cells was 2-3-fold higher than that in MCF-7 and SKBR3 cells. siRNA-mediated knockdown of PC expression in MDA-MB-231 and MDA-MB-435 cells resulted in a 50% reduction of cell proliferation, migration and in vitro invasion ability, under both glutamine-dependent and glutamine-depleted conditions. Overexpression of PC in MCF-7 cells resulted in a 2-fold increase in their proliferation rate, migration and invasion abilities. Taken together the above results suggest that anaplerosis via PC is important for breast cancer cells to support their growth and motility.
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Phatchariya
authors.initials: P
authors.lastname: Phannasil
authors.affiliation: Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Chanitra
authors.initials: C
authors.lastname: Thuwajit
authors.affiliation: Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Malee
authors.initials: M
authors.lastname: Warnnissorn
authors.affiliation: School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA5005, Australia.
authors.forename: John C
authors.initials: JC
authors.lastname: Wallace
authors.affiliation: Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacDonald
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Sarawut
authors.initials: S
authors.lastname: Jitrapakdee
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D011766:Pyruvate Carboxylase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D011766:Pyruvate Carboxylase