PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1-induced VEGF-C upregulation in breast cancer

Zhu, Chenfang; Qi, Xiao-Liang; Chen, Yaning; Sun, Bo; Dai, Yue; Gu, Yu

doi:10.1007/s00432-011-1049-2

Cited by 114 publications

(86 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Increasing amounts of evidence have shown that hypoxia-induced abnormal proliferation of PASMCs is one of the major causes for hypoxic pulmonary arterial remodeling [11,41]. The ERK1/2 and PI3K/Akt signaling pathways have been recognized to mediate a wide range of functions, including proliferation, growth, and survival [42][43][44]. Besides, it has been demonstrated that they were crucial in mediating vascular smooth muscle cell proliferation in response to hypoxia exposure [45,46].…”

Section: Discussionmentioning

confidence: 99%

Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells

Jin

Wang

Zhou

et al. 2014

Journal of Pineal Research

View full text Add to dashboard Cite

Hypoxia-induced inflammation and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) play important roles in the pathological process of hypoxic pulmonary hypertension (HPH). Melatonin possesses anti-inflammatory and antiproliferative properties. However, the effect of melatonin on HPH remains unclear. In this study, adult Sprague-Dawley rats were exposed to intermittent chronic hypoxia for 4 wk to mimic a severe HPH condition. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio, and median width of pulmonary arterioles. Melatonin attenuated the elevation of RVSP, RV/LV+S, and mitigated the pulmonary vascular structure remodeling. Melatonin also suppressed the hypoxia-induced high expression of proliferating cell nuclear antigen (PCNA), hypoxia-inducible factor-1α (HIF-1α), and nuclear factor-κB (NF-κB). In vitro, melatonin concentration-dependently inhibited the proliferation of PASMCs and the levels of phosphorylation of Akt and extracellular signal-regulated kinases1/2 (ERK1/2) caused by hypoxia. These results suggested that melatonin might potentially prevent HPH via anti-inflammatory and antiproliferative mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells

Jin

Wang

Zhou

et al. 2014

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…As demonstrated, silencing AURKA resulted in a decrease in mRNA levels of VEGF, providing an explanation for the inhibition of angiogenesis seen in the Matrigel assay. Several modes of VEGF transcriptional regulation have been cited in the literature including AKT-mediated induction in breast (22) and bladder (23) cancers. Interestingly, in our study, in addition to the effects seen on in vitro angiogenesis, silencing AURKA also resulted in decreased expression of pAKT (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma

Romain

Paul

Kim

et al. 2014

Journal of Pediatric Surgery

View full text Add to dashboard Cite

Purpose Aurora kinase A (AURKA) overexpression is associated with poor prognosis in neuroblastoma and has been described to upregulate VEGF in gastric cancer cells. However, the exact role of AURKA in the regulation of neuroblastoma tumorigenesis remains unknown. We hypothesize that AURKA-mediated stabilization of N-Myc may affect VEGF expression and angiogenesis in neuroblastoma. Therefore, we sought to determine whether inhibition of AURKA modulates neuroblastoma angiogenesis. Methods Cell viability and anchorage-independent growth were determined after silencing AURKA or after treatment with MLN8237, AURKA inhibitor. Immunofluorescence was used to determine N-Myc localization. Human umbilical vein endothelial cells (HUVECs) were used to assess angiogenesis in vitro. Real time-PCR and ELISA were performed to determine VEGF transcription and secretion, respectively. Results Knockdown of AURKA significantly reduced cell proliferation and inhibited anchorage-independent growth. It also decreased N-Myc protein levels and nuclear localization. AURKA inhibition also decreased HUVECs tubule formation along with VEGF transcription and secretion. Similarly, MLN8237 treatment decreased neuroblastoma tumorigenicity in vitro. Conclusions Our findings demonstrate that AURKA plays a critical role in neuroblastoma angiogenesis. AURKA regulates nuclear translocation of N-Myc in neuroblastoma cells, thus potentially affecting cell proliferation, anchorage-independent cell growth, and angiogenesis. Targeting AURKA might provide a novel therapeutic strategy in treating aggressive neuroblastomas.

show abstract

“…Besides playing a crucial role in regulating cell growth, proliferation and differentiation, IGF-1R and its downstream signalling pathways have been implicated in the development of resistance to endocrine and targeted therapies (Gao et al , 2012; Karamouzis and Papavassiliou, 2012). In addition, a role in tumour cell migration and metastatic potential and a direct involvement in the metastatic cascade in breast have recently been proposed (Zhu et al , 2011). Interestingly, IGF-dependent enhanced cellular proliferation has been documented in TNBCs, which can provide new targets for the so far limited therapeutic options of this sub-type that lacks expression of other druggable targets, such as ER or HER-2 (Davison et al , 2011).…”

Section: Discussionmentioning

confidence: 99%

Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

et al. 2014

View full text Add to dashboard Cite

Background:Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways.Methods:Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR.Results:IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration.Conclusions:IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies.

show abstract

PI3K/Akt and MAPK/ERK1/2 signaling pathways are involved in IGF-1-induced VEGF-C upregulation in breast cancer

Abstract: This study identified that PI3K/Akt and MAPK/ERK1/2 signaling pathways were involved in IGF-1-induced VEGF-C up-regulation and suggested their important roles in lymphatic metastasis in breast cancer.

Cited by 114 publications

References 18 publications

Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells

Melatonin attenuates hypoxic pulmonary hypertension by inhibiting the inflammation and the proliferation of pulmonary arterial smooth muscle cells

Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma

Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

Contact Info

Product

Resources

About