Mechanism of Action of Antipolyamine Therapy

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Figure 4 illustrates our ongoing research on the mechanisms of antitumor action of DFMO in breast cancer cells. We have shown that, in MDA-MB-435 cells, DFMO activates the MAPK pathway, as evidenced by increased phosphorylation of extracellular regulated kinase (ERK)-1 and ERK-2 (46). A similar effect of DFMO has been reported by us in MCF-10A human breast epithelial cells (47) and by other investigators in intestinal epithelial and melanoma cells where this effect has been connected to induction of cell-cycle arrest (48,49). We found that in MDA-MB-435 cells, activation of MAPK is causally linked to the anti-invasive action of DFMO because inhibition of ERK phosphorylation with the MEK inhibitor PD98059 reversed the effect of DFMO (Fig. 5) (46). Our results, shown in Fig. 5, also indicate that the role of the MAPK pathway in invasiveness in our experimental system depends on the specific cellular context. In the absence of concomitant DFMO administration, PD98059 treatment either had no effect on invasiveness (Fig. 5A) or exerted an anti-invasive effect (Fig. 5B), depending on whether hepatocyte growth factor was present or absent as a chemoattractant.

The activation of the MAPK pathway by DFMO is difficult to reconcile with previous reports from our and other laboratories indicating that induction of ODC overexpression also leads to increased ERK-1 and -2 phosphorylation (13,16,50). Clearly, the link between the polyamines and the MAPK pathway is complex and likely to vary, depending on the cell type and the specific stimulus to which the cells are exposed.

We have been interested in identifying mechanisms downstream of the MAPK pathway that may be responsible for the anti-invasive effect of DFMO in our system. We observed that activation of the MAPK pathway by DFMO induced a marked increase in thrombospondin-1 (TSP-1) production by MDA-MB-435 cells because the stimulation of TSP-1 by DFMO could be blocked by the MEK inhibitor PD98059 (Fig. 6) (46). TSP-1 is an extracellular matrix glycoprotein that has been found to have predominantly an antimetastatic activity, including in MDA-MB-435 breast cancer cells (51,52). It is thought that the tumor-suppressive function and antimetastatic action of TSP-1 is largely from its potent antiangiogenic effect (53). Therefore, it is conceivable

Tumor Mechanism Study Presentation

Fig. 4. Diagram summarizing the mechanism of antitumor action of DFMO in MDA-MB-435 human breast cancer cells. Activation of the mitogen-activated protein kinase pathway appears to be a central event mediating the effects of DFMO on meprin a, thrombospondin-1 (both likely to be involved in invasiveness and metastasis), and cell-cycle progression. Dotted lines indicate hypothetical connections, not yet proven experimentally.

Fig. 4. Diagram summarizing the mechanism of antitumor action of DFMO in MDA-MB-435 human breast cancer cells. Activation of the mitogen-activated protein kinase pathway appears to be a central event mediating the effects of DFMO on meprin a, thrombospondin-1 (both likely to be involved in invasiveness and metastasis), and cell-cycle progression. Dotted lines indicate hypothetical connections, not yet proven experimentally.

that at least one of the mechanisms of antimetastatic action of DFMO in our system is through suppression of angiogenesis caused by upregulation of TSP-1 through the MAPK pathway. Obviously, it will be necessary to determine whether the effect of DFMO is blocked when TSP-1 production or action is inhibited before the increase in TSP-1 can be causally linked to the anti-invasive effect of DFMO.

Recent experiments conducted in collaboration with the laboratory of Dr. Judith Bond in the Department of Biochemistry and Molecular Biology at our institution have shown that expression of the metalloprotease, meprin a, is suppressed by DFMO through activation of the MAPK pathway because meprin a expression is restored in DFMO-treated MDA-MB-435 cells with administration of the MEK inhibitor, PD98059 (54). Regulation of protease expression and activity can certainly be an important mechanism by which DFMO affects the invasive and metastatic properties of breast cancer cells. In other systems, protease expression has been shown to be elevated after induction of ODC overexpression (55,56) and inhibited in response to DFMO administration (56).

Finally, in a recent series of yet-unpublished experiments conducted in MDA-MB-435 cells, we have shown that DFMO-induced ERK phosphorylation is causally linked to

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