WNT5A-mediated  -catenin-independent signalling is a novel regulator of cancer cell metabolism

Abstract

WNT5A has been identified as an important ligand in the malignant progression of a number of tumours. Although WNT5A signalling is often altered in cancer, the ligand’s role as either a tumour suppressor or oncogene varies between tumour types and is a contemporary issue for investigators of β-catenin-independent WNT signalling in oncology. Here, we report that one of the initial effects of active WNT5A signalling in malignant melanoma cells is an alteration in cellular energy metabolism and specifically an increase in aerobic glycolysis. This was found to be at least in part due to an increase in active Akt signalling and lactate dehydrogenase (LDH) activity. The clinical relevance of these findings was strengthened by a strong correlation (P < 0.001) between the expression of WNT5A and LDH isoform V in a cohort of melanocytic neoplasms. We also found effects of WNT5A on energy metabolism in breast cancer cells, but rather than promoting aerobic glycolysis as it does in melanoma, WNT5A signalling increased oxidative phosphorylation rates in breast cancer cells. These findings support a new role for WNT5A in the metabolic reprogramming of cancer cells that is a context- dependent event.

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

“…Furthermore, my colleagues and I have found that WNT5A, signaling by the Ca 2ϩ /WNT signaling pathway in melanoma cells, also increases aerobic glycolysis, mediated by the AktmTORC1 signaling module (13). Collectively, this work suggests that WNT/Akt-mTOR signaling is an important step in controlling cancer cell metabolism in a variety of tumor types.…”

“…My colleagues and I have found that WNT5A signaling alters carbohydrate metabolism with directly opposite effects on breast cancer and melanoma cells, increasing OXPHOS in the former and aerobic glycolysis in the latter (13), which correlate with reduced and enhanced survival of patients, respectively. So, although most of the WNT signaling pathways studied to date result in enhanced aerobic glycolysis in cancer cells (Fig.…”

“…Recently, evidence has emerged that highlights a role for WNT-mediated regulation of cellular metabolism as well, including the reprogramming of tumor cell bioenergetics (12)(13)(14)(15). This review explores the evidence that components of the WNT signaling pathways regulate cellular metabolism with a specific focus on cancer cells.…”

Silencing of CerS6 increases the invasion and glycolysis of melanoma WM35, WM451 and SK28 cell lines via increased GLUT1-induced downregulation of WNT5A

“…The upregulated expression of GLUT1 decreased the expression of WNT5A, the signaling of which in malignant melanoma cells alters cellular energy metabolism and specifically increases aerobic glycolysis (33). In a recent study, WNT5A was suggested to promote melanoma cell migration/invasion via an FZD-4-β-catenin-dependent mechanism (34).…”

WNT5A and Its Receptors in the Bone-Cancer Dialogue

“…(66,67) Another study dealing with changes in energy metabolism found WNT5A to increase the aggressive behavior of melanoma cells beyond the enhancement of aerobic glycolysis. (68) In contrast, downregulation of WNT5A showed inhibitory effects on melanoma cell invasion. (69) Different studies indicate that WNT5A is regulated by the pro-inflammatory cytokine interleukin-6 (IL-6) in a p38a-MAPK-dependent manner.…”