GDNF increases cell motility in human colon cancer through VEGF–VEGFR1 interaction

Abstract

Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor, has been shown to affect cancer cell metastasis and invasion. However, the molecular mechanisms underlying GDNF-induced colon cancer cell migration remain unclear. GDNF is found to be positively correlated with malignancy in human colon cancer patients. The migratory activities of two human colon cancer cell lines, HCT116 and SW480, were found to be enhanced in the presence of human GDNF. The expression of vascular endothelial growth factor (VEGF) was also increased in response to GDNF stimulation, along with VEGF mRNA expression and transcriptional activity. The enhancement of GDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Our results also showed that the expression of VEGF receptor 1 (VEGFR1) was increased in response to GDNF stimulation, whereas GDNF-induced cancer cell migration was reduced by a VEGFR inhibitor. The GDNF-induced VEGF expression was regulated by the p38 and PI3K/Akt signaling pathways. Treatment with GDNF increased nuclear hypoxia-inducible factor 1 a (HIF1a) accumulation and its transcriptional activity in a time-dependent manner. Moreover, GDNF increased hypoxia responsive element (HRE)-containing VEGF promoter transcriptional activity but not that of the HRE-deletion VEGF promoter construct. Inhibition of HIF1a by a pharmacological inhibitor or dominant-negative mutant reduced the GDNF-induced migratory activity in human colon cancer cells. These results indicate that GDNF enhances the migration of colon cancer cells by increasing VEGF-VEGFR interaction, which is mainly regulated by the p38, PI3K/Akt, and HIF1a signaling pathways.

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

“…Importantly, BDNF has been reported to be a potent angiogenic factor that facilitates tumor growth by promoting VEGF expression and angiogenesis in hepatocellular carcinoma (Lam et al 2011). Recently, we also reported that VEGF-VEGF receptor interaction increases cell motility in human colon cancer (Huang et al 2014b). The present results support results described in previous reports that VEGF is not only secreted from colon cancer in response to BDNF, but it also causes autocrine-paracrine signaling to further induce HO-1.…”

“…4C). We previously demonstrated that transfection with VEGF-luciferase reporter increases VEGF transcriptional activity after stimulation (Huang et al 2014b). The VEGF-luciferase reporter gene assay was also used to examine the molecular mechanism of BDNFinduced VEGF expression.…”

“…VEGF-targeted therapy benefits patients with advanced-stage malignancies in colon cancer (Ellis & Hicklin 2008). During a recent study we determined that VEGF-VEGF receptor interaction promotes colon cancer motility (Huang et al 2014b). Modulation of VEGF function may contribute to a successful therapeutic treatment of colon cancer and may be applied as a prognostic marker in colon cancer.…”

Gastric electrical stimulation improves enteric neuronal survival

“…A previous study indicated that GDNF and brain-derived neurotrophic factor expression levels are upregulated and that cellular apoptosis is attenuated by acupuncture in the hippocampi of rats experiencing hypoxia-ischemia (23). Furthermore, GDNF has a neurotrophic effect on diabetes-induced neuronal apoptosis in the hippocampus (24) and enhances the migration of colon cancer cells (25) via the PI3K/Akt pathway.…”

Neurotrophic Factors and Their Potential Applications in Tissue Regeneration

“…Specifically they have been linked to the growth of neuroblastoma (Komminoth et al 1996), breast cancer (Banerjee et al 2012; Ding et al 2014), small cell lung cancer (Rudin et al 2014), thyroid cancer (Hong et al 2008; Wells and Santoro 2009), pancreatic cancer (Donahue and Hines 2009) and testicular cancer (Sariola and Meng 2003). GDNF promotes perineural invasion and metastasis of brain tumor (Ilhan-Mutlu et al 2013), head and neck squamous cell carcinoma (Roh et al 2015), glioma (Shabtay-Orbach et al 2014), pancreatic cancer (He et al 2014; Wang et al 2014b) and colon cancer (Huang et al 2014). GDNF family members also increase resistance to the chemotherapy in the prostate (Huber et al 2015) and breast cancer (Ding et al 2014; Morandi et al 2013), while reduction of GDNF level decreased metastasis of mammary gland cancer and related pain in the bone of rat (Meng et al 2015).…”