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. Author manuscript; available in PMC: 2021 Apr 1.
Published in final edited form as: Semin Cancer Biol. 2019 Nov 2;61:158–166. doi: 10.1016/j.semcancer.2019.10.016

Figure 4. Iron homeostasis disruption in HLRCC.

Figure 4.

Fumarate accumulates at millimolar (mM) concentration in HLRCC cells. The accumulated fumarate drives constitutive NRF2 activation, which promoter the transcription of ferritin light (FTL) and ferritin heavy (FTH1) genes. Fumarate also inhibits iron regulatory proteins (IRPs) ability to repress FTL and FTH1 mRNA translation, resulting in high intracellular ferritin level. This high intracellular ferritin can sequester free iron, resulting in a drop in labile iron pool. The high ferritin level also indirectly activates FOXM1 transcription factor, which drive a sustained proliferative signaling. Iron is an essential element in many cellular processes. HLRCC cells rely on ferritinophagy to release ferritin stored iron. Fumarate was also shown to indirectly inhibit AMP kinase (AMPK), which in turn indirectly inhibit divalent metal transporter 1 (DMT1) expression. This prevents the efflux of iron from endosome into the cytoplasm, further reduces the labile iron pool. The low labile iron pool, causes IRPs to repress HIF2A translation, resulting in specific activation of HIF1A. Red colored arrow indicates that the pathway is upregulated in HLRCC cells. Blue colored arrow indicates that the pathway is down regulated in HLRCC cells. Green colored arrow indicates that the pathway is required in HLRCC cells. Dotted line indicates indirect mechanism. Solid line indicates that direct mechanism has been reported.