Abstract
Aberrant regulation of WNT/β-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/β-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/β-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/β-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/β-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.
Highlights
The importance of WNT signaling in metazoans cannot be underestimated; the pathways are essential in embryonic development, coordinating correct tissue patterning and for homeostasis in adult tissues
We demonstrate that the WNT/ β-catenin pathway has profound effects on melanoma cell invasion, metastasis and metabolic status between tumor cells depending on PTEN expression status
We provide evidence that a reduction in PTEN expression in melanoma cells markedly alters their phenotypic response to WNT/β-catenin signaling by reprogramming distinct metabolic signatures, which is underpinned by changes in mitochondrial activity in PTENWT, but not in PTENMut cells
Summary
The importance of WNT signaling in metazoans cannot be underestimated; the pathways are essential in embryonic development, coordinating correct tissue patterning and for homeostasis in adult tissues. Understanding how WNT signaling affects cells and tissues has far reaching implications in animal biology. The pathways do not function in an autonomous manner, but rather exist in a signaling network where there is concomitant cross-talk and regulation between the β-catenin-dependent, and -independent pathways.[2] The WNT/β-catenin pathway results in the stabilization of a cytoplasmic pool of β-catenin that would otherwise be marked for proteasomal-mediated degradation by a destruction complex, composed of (among other proteins) APC (encoded by APC), AXIN-1/2 (encoded by AXIN1/2) and GSK-3β (encoded by GSK3B). Upon binding to receptors of the Frizzled (FZD) family and the co-receptors, LRP5/6, extracellular WNT stimulation transmits a signal to the intracellular Disheveled (DVL) adaptor, which inhibits the destruction complex and allows nuclear translocation of stabilized β-catenin to activate gene transcription. Β-catenin acts as a cofactor with transcription factor/lymphoid enhancer-binding element transcription factors to stimulate expression of WNT target genes such as AXIN2 and MYC.[3,4,5]
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