Figure 8
Working model portraying the effects of WNT/β-catenin signaling in PTENWT melanoma cells under nutrient starvation conditions. (a) In the absence of a WNT ligand that signals via the WNT/β-catenin pathway, β-catenin is targeted by a destruction complex (comprising CK1, SCF, GSK-3β, AXIN and APC) for proteasome-mediated degradation. Under nutrient starvation conditions (such as in large solid tumors), PTEN drives increased autophagy. PTEN blocks PI3K-mediated activation of AKT (PKB), where AKT negatively regulates autophagy in response to mitogens (in reality occurring through activation of mTOR; not shown). This triggers autophagy addiction in PTEN expressing tumors, which does not occur in PTENMut melanomas. (b) In response to a WNT/β-catenin signaling ligand, the seven-transmembrane domain FZD receptors (blue/brown color in schematic) and LRP5/6 receptor complex, results in activation of DVL, which in turn inactivates the destruction complex. Cytoplasmic β-catenin then accumulates and is eventually translocated to the nucleus, where it interacts with transcription factor/lymphoid enhancer-binding element transcription factors to activate/repress expression of WNT target genes including SQSTM1 (gene encoding p62), which is transcriptionally repressed in response to β-catenin signaling. p62 is an autophagy adaptor that facilitates the autophagic degradation of ubiquitinated protein aggregates. We propose that inhibition of autophagy by WNT/β-catenin signaling in autophagy addicted cancer cells, inhibits mitophagy leading to nonselective mitochondrial fusion. This results in a highly networked, yet dysfunction mitochondrial population with significantly reduced cellular metabolic capacity, which negatively affects tumor cell behavior such as motility and metastasis.
