Heparin plays a key regulatory role via a p53/FAK‐dependent signaling in melanoma cell adhesion and migration

Abstract

SummaryHeparin and its various derivatives affect cancer progression in humans. In this study, we show that heparin uptaken intracellularly by melanoma cells activated a signaling cascade, which in turn inhibited melanoma cell adhesion and migration. The reduced ability of M5 cells to adhere onto the fibronectin (FN) substrate was directly correlated to a decrease in the expression of focal adhesion kinase (FAK), which is a key regulator of melanoma motility. Cell treatment with heparin caused a marked downregulation in FAK expression (P 0.01). This is followed by an analogous inhibition of both constitutive and FN-induced FAK Y397-phosphorylation (P 0.01). Moreover, heparin stimulated the p53 expression (P 0.001) of M5 cells and its increased accumulation in the nucleus. This favors a decrease in FAK promoter activation and explains the reduced FAK transcript and protein levels. In conclusion, the results of this study clearly demonstrate that the action of heparin in the regulation of melanoma cell adhesion and migration involves a p53/FAK/signaling pathway, which may be of importance in molecular targeted therapy of the disease.

Fibronectin promotes directional persistence in fibroblast migration through interactions with both its cell-binding and heparin-binding domains

“…4C). This finding suggests that heparin does not influence migration speed through changes in FN conformation, but needs to be present in the medium to be effective 38 , perhaps by acting intracellularly as previously suggested 46 . Interestingly, a closer look at the effects of soluble Hep2 and heparin on adhesion cluster formation revealed differences: a considerable reduction in the fraction of cells presenting polarized protrusions was noted in presence of soluble heparin, but not of soluble Hep2 (Supplemental Fig.…”

The Roles of Angiogenesis in Malignant Melanoma: Trends in Basic Science Research over the Last 100 Years

“…Macrophages possibly add fuel to the fire bringing greater quantities of VEGF to the tumour site setting up new VEGF gradients favoring tumour growth, which in turn may upregulate MMPs and therefore metastatic behaviour. Heparin-treated tumour cells demonstrate reduced cell adhesion and migration [86], and given that heparin-binding sites are spliced during synthesis of VEGF isoforms, investigating how heparin may affect the efficacy of VEGF isoforms on tumour growth in vitro would be intriguing.…”

IGF-I/EGF and E2 signaling crosstalk through IGF-IR conduit point affects breast cancer cell adhesion

“…To examine the putative participation of FAK signaling on the IGF-I-/EGF-dependent adhesion, we transfected MCF-7 cells with FAK siRNA (siFAK) designed according to Hong et al, (2006) [44] and demonstrated to be specific for the FAK gene [45]. As shown in Figs.…”

“…siRNA MCF-7 cells in suitable dilution plated in T25 flasks in serum and antibiotics free DMEM, and incubated with siRNA (100 nM) sequences specific for the FAK [44,45]and IGF-IR gene (ON-TARGET plus SMART pool siRNA by Dharmacon)and with siRNA negative control sequences (siscramble). Specific siRNA (Invitrogen) and Lipofectamine TM 2000 (Invitrogen) (1μl/50μl medium) were added to Opti-MEM © (Invitrogen) for 5min at room temperature.…”