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. Author manuscript; available in PMC: 2016 Mar 15.
Published in final edited form as: Adv Cancer Res. 2014;123:35–65. doi: 10.1016/B978-0-12-800092-2.00002-2

Figure 2.1.

Figure 2.1

Molecular basis for the antitumor activity of 4-MU. Binding of HA receptors to cell surface HA receptors, CD44 and RHAMM, triggers a variety of signaling events, including complex formation between HA receptors and growth factor receptor protein tyrosine kinases, and activation of downstream effectors such as Akt, NFkB, src, Erk, Ras/Raf/Rac-1. These signaling events culminate in the expression of a variety of inflammatory cytokines, VEGF, matrix metalloproteinases (MMP-2, MMP-9), as well as HA synthase and CD44/RHAMM. By inducing these signaling events and downstream effectors, HA drives cell survival, proliferation, epithelial–mesenchymal interaction, invasion, and motility which lead to tumor growth and progression. Since 4-MU inhibits HA synthesis, it blocks the first event in this signaling cascade and hence shows potent antitumor and antimetastatic efficacy.