Figure 4.
Metastasis suppressors KAI1, NDRG2, and the tumor suppressor, p53, are regulated by cellular iron levels. KAI1 is a tetraspanin that resides on the cell membrane and has the ability to associate with c-Src to inhibit key molecules such as p130Cas, FAK, and paxillin that are involved in its regulation of cell motility and migration in cancer cells. It is known that NDRG1 is also able to down-regulate p130Cas in an Src-dependent manner, and in turn, it could possibly regulate KAI1. The established tumor suppressor p53 may also play a role in regulating KAI1, by increasing its transcription. The involvement of iron can be understood by evidence demonstrating that iron depletion by chelators such as Dp44mT increases NDRG1 levels in the presence of p53. NDRG2 is also up-regulated by cellular iron depletion and may inhibit cancer cell proliferation and survival by blocking STAT-3 activation in a p38 MAPK-dependent manner.