Durable Response of Spinal Chordoma to Combined Inhibition of IGF-1R and EGFR

Aleksic, Tamara; Browning, Lisa; Woodward, Martha; Phillips, R E; Page, Suzanne; Henderson, Shirley; Athanasou, Nicholas A.; Ansorge, Olaf; Whitwell, Duncan; Pratap, Sarah; Hassan, A. Bassim; Middleton, Mark R.; Macaulay, Valentine M.

doi:10.3389/fonc.2016.00098

Cited by 31 publications

(27 citation statements)

References 49 publications

(50 reference statements)

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“…Previous studies have shown that renal tumor-associated gene VHL plays a decisive role in regulating HIF expression 13,14 . Similarly, research data also shows that there are many links between FLCN and HIF1α 8,15 . Our pretest result indicated that the FLCN gene acts as a regulator of renal tumors and its knockdown resulted in a significant increase in HIF2α protein levels.…”

Section: Introductionmentioning

confidence: 81%

mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

Zhao

Cui

et al. 2020

Preprint

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Clear cell renal cell carcinoma (ccRCC), as the most important type of renal carcinoma, has a high incidence and easy metastasis. Folliculin (FLCN) was identified as a tumor suppressor gene. Its deletions and mutations are associated with a potential risk of kidney cancer. At present, the specific molecular mechanism of FLCN-induced proliferation, invasion and migration in clear cell renal cell carcinoma remains elusive.In this study, we demonstrated that FLCN controled cell proliferation, invasion and migration through PI3K/mTORC2 pathway. FLCN combined with HIF2α in various normal and cancerous renal cells, and mTORC2 mediate FLCN effectively alleviated the deterioration of renal cancer cells by degrading HIF2α. Silencing of FLCN showed promotion of HIF2α protein expression, which in turn led to an increase in downstream target genes Cyclin D1 and MMP9. Moreover, when interfering with siFLCN, HIF2α degradation rate was delayed, and the time of entry into the nucleus was advanced. Taken together, our study illustrated that mTORC2 promoted the specific molecular mechanism of HIF2α by down-regulated FLCN, and might be a new therapeutic target against renal cancer progression. Abbreviations:FLCN: folliculin VHL: Von Hippel -Lindau MMP9: matrix metalloproteinase 9 CHX: cycloheximide ccRCC: clear cell renal cell carcinoma IntroductionRenal cell carcinoma is a malignant tumor originating in the renal tubular epithelial system, and most of which are clear cell renal cell carcinoma (~75%) 1 . Cell viability is important for various physiological processes such as embryonic development, angiogenesis, and tumor proliferation, invasion and metastasis. Birt-Hogg-Dubé syndrome is caused by inactivating mutations of FLCN, a tumor suppressor gene which encodes folliculin 2 . Common causes of Birt-Hogg-Dubé syndrome are lung cyst, spontaneous pneumothorax, skin fibrofolliculomas and renal cancer 3 . It is also reported that inactivation of FLCN is an initial step in the development of renal tumors in BHD 4 . Work by Sok Kean Khoo and Laura S. Schmidt have confirmed a tumor suppressor role for FLCN [5][6][7] . Similarly the FLCN-deficient animal models 8 showed activated mTOR and its downstream pathway effectors 9 . These paper suggested that FLCN-deficient kidney tumors showed activation of mTOR and AKT 10 . And this regulation mechanism is also established in humans 2,11,12 .Hypoxia-inducible factor (HIF) is a crucial mediator of hypoxic adaptation. Previous studies have shown that renal tumor-associated gene VHL plays a decisive role in regulating HIF expression 13,14 . Similarly, research data also shows that there are many links between FLCN and HIF1α 8,15 . Our pretest result indicated that the FLCN gene acts as a regulator of renal tumors and its knockdown resulted in a significant increase in HIF2α protein levels. Cyclin D1 and MMP9 have been identified as HIF2α-regulated genes which can mediate cancer cell proliferation and invasion [16][17][18] .In this study, we hypothesized that FLCN may regulate HIF2α through bindi...

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Section: Introductionmentioning

confidence: 81%

mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

Zhao

Cui

et al. 2020

Preprint

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“…Furthermore, immunofluorescence demonstrated that increased MG63 cell growth correlated with β-catenin colocalizing with IGF-IR to the membrane, cytoplasm and nucleus. Previously in a number of chordoma biopsies, Aleksic et al detected IGF-1R in the plasma membrane and cytoplasm which was expressed more strongly in recurrent tumor than the primary ( 56 ). Furthermore, in the same cohort Aleksic et al had identified heterogeneous nuclear IGF-1R, which has been linked with sensitivity to IGF-1R inhibition ( 56 ).…”

Section: Discussionmentioning

confidence: 98%

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

et al. 2018

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Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth (p ≤ 0.001). IGF-I was shown to increase biglycan expression (p ≤ 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells (p ≤ 0.001; p ≤ 0.01, respectively). These effects were executed through the IGF-IR receptor whose activation was strongly attenuated (p ≤ 0.01) in biglycan-deficient MG63 cells. Biglycan, previously shown to regulate Wnt/β-catenin pathway, was demonstrated to induce a significant increase in β-catenin protein expression evident at cytoplasmic (p ≤ 0.01), membrane (p ≤ 0.01), and nucleus fractions in MG63 cells (p ≤ 0.05). As demonstrated by immunofluorescence, increase in β-catenin expression is attributed to co-localization of biglycan with the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) resulting in attenuated β-catenin degradation. Furthermore, applying anti-β-catenin and anti-pIGF-IR antibodies to MG-63 cells demonstrated a cytoplasmic and to the membrane interaction between these molecules that increased upon exogenous biglycan treatment. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I-dependent ERK1/2 activation, (p ≤ 0.001). In summary, we report a novel mechanism where biglycan through a LRP6/β-catenin/IGF-IR signaling axis enhances osteosarcoma cell growth.

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“…It has been reported that nuclear IGF-IR is a feature of pre-invasive lesions and invasive cancers including prostate, renal and breast cancers, and an association between nuclear IGF-IR and adverse prognosis was identified in renal cancer [79]. Subsequent data did associate nuclear IGF-IR with proliferation, tumorigenicity, resistance to EGFR inhibition and clinical response to therapeutic anti-IGF-IR antibodies, which suggests that IGF-IR nuclear import has biological significance and may contribute directly to IGF-IR function [79,[85][86][87][88][89][90].…”

Section: The Nuclear Translocation Of the Igf-ir And Irs And Its Signmentioning

confidence: 99%

New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

Janssen

2020

Cells

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Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-II (IGF-II) play a crucial factor in the growth, differentiation and survival of cells in health and disease. IGF-I and IGF-II primarily activate the IGF-I receptor (IGF-IR), which is present on the cell surface. Activation of the IGF-IR stimulates multiple pathways which finally results in multiple biological effects in a variety of tissues and cells. In addition, activation of the IGF-IR has been found to be essential for the growth of cancers. The conventional view in the past was that the IGF-IR was exclusively a tyrosine kinase receptor and that phosphorylation of tyrosine residues, after binding of IGF-I to the IGF-IR, started a cascade of post-receptor events. Recent research has shown that this view was too simplistic. It has been found that the IGF-IR also has kinase-independent functions and may even emit signals in the unoccupied state through some yet-to-be-defined non-canonical pathways. The IGF-IR may further form hybrids with the insulin receptors but also with receptor tyrosine kinases (RTKs) outside the insulin-IGF system. In addition, the IGF-IR has extensive cross-talk with many other receptor tyrosine kinases and their downstream effectors. Moreover, there is now emerging evidence that the IGF-IR utilizes parts of the G-protein coupled receptor (GPCR) pathways: the IGF-IR can be considered as a functional RTK/GPCR hybrid, which integrates the kinase signaling with some IGF-IR mediated canonical GPCR characteristics. Like the classical GPCRs the IGF-IR can also show homologous and heterologous desensitization. Recently, it has been found that after activation by a ligand, the IGF-IR may be translocated into the nucleus and function as a transcriptional cofactor. Thus, in recent years, it has become clear that the IGF-IR signaling pathways are much more complex than first thought. Therefore a big challenge for the (near) future will be how all the new knowledge about IGF-IR signaling can be translated into the clinical practice and improve diagnosis and treatment of diseases.

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Durable Response of Spinal Chordoma to Combined Inhibition of IGF-1R and EGFR

Cited by 31 publications

References 49 publications

mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

mTORC2 mediate FLCN-induced HIF2α nuclear import and proliferation of clear cell renal cell carcinoma

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

New Insights from IGF-IR Stimulating Activity Analyses: Pathological Considerations

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