Angiopoietin-like 4 promotes melanoma cell invasion and survival through aldolase A.

In the present study, the association between angiopoietin-like 4 (ANGPTL4) and aldolase A (ALDOA) in human melanoma cell invasion and survival was investigated. Overexpression and knockdown of ANGPTL4 were respectively performed in WM-115 and WM-266-4 cells. ALDOA expression at both the mRNA and the protein levels as well as the gene promoter activities were increased and decreased in parallel with overexpression and knockdown of ANGPTL4 in the melanoma cells, which was blocked by selective protein kinase C (PKC) inhibitor and restored by PKC agonist, respectively. ANGPTL4 overexpression significantly increased cell invasion and matrix metalloproteinase-2 (MMP-2) expression and decreased cell apoptosis against cisplatin in WM-115 cells, which was reversed by knocking down ALDOA. In WM-266-4 cells, knockdown of ANGPTL4 decreased cell invasion and MMP-2 expression and increased cell apoptosis against cisplatin, which was reversed by overexpression of ALDOA. In conclusion, this study demonstrates that ANGPTL4 upregulates ALDOA expression in human melanoma cells at the ALDOA gene promoter/transcriptional level through a PKC-dependent mechanism, and that ALDOA is a critical mediator of the promoting effect of ANGPTL4 on melanoma cell invasion, likely through upregulating the MMP-2 expression. Additionally, our results suggest that ALDOA plays an important role in ANGPTL4-enhanced melanoma cell survival against apoptotic stress, which implicates ANGPTL4 and ALDOA in the development of melanoma chemoresistance.