title: Serum deprivation confers the MDA-MB-231 breast cancer line with an EGFR/JAK3/PLD2 system that maximizes cancer cell invasion.
abstract: Our laboratory has reported earlier that in leukocytes, phospholipase D2 (PLD2) is under control of Janus kinase 3 (JAK3), which mediates chemotaxis. Investigating JAK3 in cancer cells led to an important discovery as exponentially growing MDA-MB-231 human breast cancer cells, which are highly proliferative and metastatic, did not substantially use JAK3 to activate PLD2. However, in 2-h or 16-h starved cell cultures, JAK3 switches to a PLD2-enhancing role, consistent with the needs of those cells to enter a "survival state" that relies on an increase in PLD2 activity to withstand serum deprivation. Using a small-molecule tyrosine kinase inhibitor, the flavonoid 4',5,7-trihydroxyflavone (apigenin), as well as RNA silencing, we found that the invasive phenotype of MDA-MB-231 cells is mediated by PLD2 under direct regulation of both JAK3 and the tyrosine kinase, epidermal growth factor receptor (EGFR). Furthermore, serum-deprived cells in culture show an upregulated EGFR/JAK3/PLD2-PA system and are especially sensitive to a combination of JAK3 and PLD2 enzymatic activity inhibitors (30nM apigenin and 300nM 5-fluoro-2-indolyl des-chlorohalopemide (FIPI), respectively). Thus, a multi-layered activation of cell invasion by two kinases (EGFR and JAK3) and a phospholipase (PLD2) provides regulatory flexibility and maximizes the aggressively invasive power of MDA-MB-231 breast cancer cells. This is especially important in the absence of growth factors in serum, coincidental with migration of these cells to new locations.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, Dayton, OH 45435, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Samuel
authors.initials: S
authors.lastname: Kantonen
authors.forename: Julian
authors.initials: J
authors.lastname: Gomez-Cambronero
mesh_terms: D047310:Apigenin / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004294:Domperidone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C546435:5-fluoro-2-indolyldeschlorohalopemide; D016895:Culture Media, Serum-Free; D007211:Indoles; D004294:Domperidone; D047310:Apigenin; D066246:ErbB Receptors; D053616:Janus Kinase 3; C105606:phospholipase D2; D010739:Phospholipase D