Serum Deprivation Confers the MDA-MB-231 Breast Cancer Line with an EGFR/JAK3/PLD2 System That Maximizes Cancer Cell Invasion

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 (30 nM apigenin and 300 nM 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (98 K)Download as PowerPoint slideHighlights► Cell invasion of cancer cells relies on JAK3 and PLD2. ► PLD2 and JAK3 activities are enhanced in serum-deprived cultures. ► The flavonoid apigenin is a strong inhibitor of PLD2, JAK3, and cell invasion. ► An EGFR/JAK3/PLD2 system exists under serum deprivation or “cell survival mode”. ► The mechanism explains the aggressive invasiveness of MDA-MB-231 cancer cells.