Multiple receptor tyrosine kinases regulate HIF-1α and HIF-2α in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors

Abstract

Novel treatment approaches are needed for children with advanced neuroblastoma. Studies with neuroblastoma cells have indicated the presence of a hypoxiadriven vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-1 autocrine loop modulating hypoxiainducible factor-1alpha (HIF-1a). Whether other receptor tyrosine kinases (RTKs) are capable of modulating HIF1a levels and whether RTKs can regulate HIF-2a as well is largely unknown. We evaluated neuroblastoma cell lines for expression of various RTKs. Although cell lines were heterogeneous in the expression of VEGFR-1, -3, c-Kit and RET, most cells expressed PDGFR-a and -b. Ligandinduced activation of multiple RTKs upregulated HIF-1a levels, whereas activation of VEGFR-1 alone upregulated HIF-2a. Multitargeted tyrosine kinase inhibitor sunitinib reduced hypoxia-induced rises in HIF-1a and HIF-2a through mechanisms involving effects on both mRNA levels and protein stability. In addition, sunitinib and sorafenib had direct effects on tumor cell viability in vitro. In a neuroblastoma xenograft model, tumor growth inhibition by sunitinib was associated with inhibition of angiogenesis and reduced HIF-1a levels. These findings show that multiple RTKs may regulate the HIF axis in normoxia and hypoxia and suggest that multikinase inhibitors may exert antiangiogenic effects not only by direct effects on endothelial cells, but also by blocking compensatory hypoxia-and ligand-induced changes in HIF-1a and HIF-2a.

Sorafenib Inhibits Hypoxia-Inducible Factor-1α Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma

“…14, 15). While the blocking of VEGFR and PDGFR may account for the antiangiogenesis effect of sorafenib in HCC, sorafenib, and sunitinib can also inhibit the expression of HIF-1a in neuroblastoma and colon cancer cells (16,17). These findings may suggest the potential role of HIF-1a in mediating antiangiogenesis effect of sorafenib in HCC.…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…It is suggested that both PI3K and MAPK pathways can mediate this phenomenon [167]. The crosstalk between RET and HIF-1α has been described also in neuroblastoma cells, where activation of RET induced by its ligand GDNF increases HIF-1α protein levels [130]. In turn, expression of GDNF was reported to be increased in hypoxic rat astrocytes [168].…”

“…Recent studies using neuroblastoma cells indicated that VEGF-induced activation of VEGFR-1 leads to increase of both HIF-1α and HIF-2α protein levels [130]. In clinical neuroblastoma specimens, HIF-2α protein levels positively correlate with VEGF expression and poor patient outcome [131].…”

“…Increased expression potentially mediated by HIF-1α [130,168] Non-small cell lung cancer (NSCLC), RCC, breast cancer, prostate cancer, glioblastoma cells EGFR mRNA translation through activated HIF-2α [76,79] 786-0 ccRCC cells EGFR Delayed receptor endocytosis [81] 786-O ccRCC EGFR Ligand-independent activation through elevated expression of CAV1 [86] T-47D and MDA-MB-468 breast cancer cells, HEK293 human embryonic kidney cells…”

The Involvement of the ERK-Hypoxia-Angiogenesis Signaling Axis and HIF-1 in Hepatocellular Carcinoma

“…The approval of sorafenib, a Raf inhibitor and anti-angiogenic agent, as single agent against HCC probably demonstrates this principle. Although, the effect of sorafenib on HIF-1 activity has not been directly studied in HCC, sorafenib has been shown to interfere with the HIF pathway in models of melanoma and neuroblastoma (Kumar et al, 2007;Nilsson et al, 2010). It is possible that combination of sorafenib with other agents that also target ERK (such as kaempferol or other naturally occurring substances with similar properties), HIF-1 (such as MTD) or VEGF (such as bevacizumab or inhibitors of the VEGF receptor) could be more efficient in treating HCC and preventing acquirement of resistance (Fig.…”