scholarly journals Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

2020 ◽  
Vol 21 (3) ◽  
pp. 1058
Author(s):  
Akane Yamagishi ◽  
Yuki Ikeda ◽  
Masayoshi Ikeuchi ◽  
Ryuzaburo Yuki ◽  
Youhei Saito ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Cancer Progression ◽  
Spindle Assembly Checkpoint ◽  
Aurora B ◽  
Insulin Like Growth Factor ◽  
Altered Expression ◽  
M Phase ◽  
Igf1r Inhibitor ◽  
The Impact

The insulin-like growth factor 1 receptor (IGF1R) is a receptor-type tyrosine kinase that transduces signals related to cell proliferation, differentiation, and survival. IGF1R expression is often misregulated in tumor cells, but the relevance of this for cancer progression remains unclear. Here, we examined the impact of IGF1R inhibition on cell division. We found that siRNA-mediated knockdown of IGF1R from HeLa S3 cells leads to M-phase delays. Although IGF1R depletion causes partial exclusion of FoxM1 from the nucleus, quantitative real-time PCR revealed that the transcription of M-phase regulators is not affected by decreased levels of IGF1R. Moreover, a similar delay in M phase was observed following 2 h of incubation with the IGF1R inhibitors OSI-906 and NVP-ADW742. These results suggest that the M-phase delay observed in IGF1R-compromised cells is not caused by altered expression of mitotic regulators. Live-cell imaging revealed that both prolonged prometaphase and prolonged metaphase underlie the delay and this can be abrogated by the inhibition of Mps1 with AZ3146, suggesting activation of the Spindle Assembly Checkpoint when IGF1R is inhibited. Furthermore, incubation with the Aurora B inhibitor ZM447439 potentiated the IGF1R inhibitor-induced suppression of cell proliferation, opening up new possibilities for more effective cancer chemotherapy.

Effect of insulin-like growth factor 1 receptor inhibitor on sensitization of head and neck cancer cells to cetuximab and methotrexate

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6079-6079
Author(s):  
H. Hatakeyama ◽  
J. Parker ◽  
D. Wheeler ◽  
P. Harari ◽  
S. Levy ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Head And Neck ◽  
Cell Lines ◽  
Radiation Resistance ◽  
Chemotherapeutic Agents ◽  
Insulin Like Growth Factor ◽  
Igf1r Inhibitor

6079 Background: Insulin-like growth factor 1 receptor (IGF1R) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and IGF1R inhibitors have been shown to modulate sensitivity to selected chemotherapeutic agents and radiation. The combination effects of an IGF1R inhibitor, MK-0646, with cetuximab or cytotoxic agents that are commonly used in the treatment of recurrent and/or metastatic HNSCC were examined in cetuximab resistant and sensitive HNSCC cell lines. Methods: The cell lines, SCC1 and its cetuximab-resistant clone 1Cc8, were treated with MK-0646, cetuximab or methotrexate, and a combination of MK-0646 and each anti-cancer drug (MK-0646 was supplied by Merck & Co., Inc.). The effect of treatments on cell proliferation and anti-tumor activity was determined using MTS assay in vitro and in vivo using mouse xenografts generated from the cell lines. Overall changes in the gene and protein expressions with the treatments were determined by DNA microarrays and western blots. Results: The IGF1R inhibitor, MK-0646, showed high-sensitivity in vitro xenograft model in SCC1 as monotherapy and increased sensitivity to cetuximab in SCC1 and to methotrexate in 1Cc8 in combination. However, MK-0646 did not inhibit cell proliferation in vitro and in vivo in 1Cc8. The gene expression array and western blot analyses showed that MK-0646 decreased expression of AKT and dihydrofolate reductase (DHFR), a target of methotrexate. Increased expressions of AKT and DHFR have been shown to associate with cetuximab and methotrexate resistance as well as radiation resistance. Conclusions: The development of tolerance in response to the IGF1R inhibitor and cetuximab is common. Whereas IGF1R inhibitors may have little therapeutic impact in cetuximab resistant, the IGF1R inhibitor may modulate response to selected chemotherapeutic agents and to radiation. The IGF1R inhibitor appears to enhance cetuximab and methotrexate response, and modulates genes associated with radiation resistance thereby providing alternative regimens for recurrent and refractory HNSCC patients who have developed resistance to initial therapies. No significant financial relationships to disclose.

scholarly journals IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Chenyang Qiao ◽  
Wenjie Huang ◽  
Jie Chen ◽  
Weibo Feng ◽  
Tongyue Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Cancer Metastasis ◽  
Combined Treatment ◽  
Insulin Like Growth Factor ◽  
Atp Citrate Lyase ◽  
Citrate Lyase ◽  
Elevated Expression ◽  
Igf1r Inhibitor ◽  
Colorectal Cancer Metastasis

AbstractMetastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

Ethanol-Induced Inhibition of Cell Proliferation Is Modulated by Insulin-Like Growth Factor-I Receptor Levels

1996 ◽  
Vol 20 (5) ◽  
pp. 961-966 ◽  
Author(s):  
Mariana Resnicoff ◽  
Shijun Cui ◽  
Domenico Coppola ◽  
Jan B. Hoek ◽  
Raphael Rubin
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Growth Factor I

scholarly journals Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression?

2012 ◽  
Vol 70 (15) ◽  
pp. 2657-2675 ◽  
Author(s):  
Jessica L. Bell ◽  
Kristin Wächter ◽  
Britta Mühleck ◽  
Nikolaos Pazaitis ◽  
Marcel Köhn ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Binding Proteins ◽  
Insulin Like Growth Factor ◽  
Mrna Binding Proteins ◽  
Mrna Binding

Decreased Circulating Insulin-Like Growth Factor 1 Levels Are Associated with Cardiac Diastolic Dysfunction in Small for Gestational Age Infants

2018 ◽  
Vol 35 (12) ◽  
pp. 1178-1185
Author(s):  
Shoko Yamazaki ◽  
Haruka Obinata ◽  
Akira Hachiya ◽  
Motoko Kamiya ◽  
Noriko Motoki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Diastolic Dysfunction ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Linear Regression Analysis ◽  
Entire Population ◽  
Doppler Imaging ◽  
Multivariate Linear Regression Analysis ◽  
Insulin Like Growth Factor ◽  
The Impact

Objective To evaluate the impact of serum insulin-like growth factor-1 (IGF-1) levels on cardiac function in small for gestational age (SGA) infants. Study Design This is a prospective, observational study. Serum IGF-1 levels at birth and echocardiography measurements at 1 week of age were compared between SGA and appropriate for gestational age (AGA) infants. Results Thirty-one SGA infants and 27 AGA infants were enrolled. Serum IGF-1 levels were lower in the SGA infants than in the AGA infants. SGA infants had lower mitral lateral annular systolic (S') and early diastolic (E') tissue Doppler imaging velocities compared with AGA infants (S', 5.1 ± 0.9 vs 5.7 ± 1.2 cm/s; E', 6.1 ± 1.5 cm/s vs 7.1 ± 1.3 cm/s; p < 0.05). Serum IGF-1 levels positively correlated with E' velocity in the entire population (r = 0.44, p < 0.001) and in SGA infants (r = 0.39, p < 0.05). In multivariate linear regression analysis, serum IGF-1 and S' velocity were independently associated with E' velocity in the entire population and in SGA infants. Conclusion Decreased serum IGF-I levels could account for cardiac diastolic dysfunction in SGA infants.

Overexpressed miR-375-Loaded Restrains Development of Cervical Cancer Through Down-Regulation of Frizzled Class Receptor 4 (FZD4) with Liposome Nanoparticle as a Carrier

2021 ◽  
Vol 17 (9) ◽  
pp. 1882-1889
Author(s):  
Suqin Wang ◽  
Lina Xu ◽  
Zhiqiang Zhang ◽  
Ping Wang ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
M Phase ◽  
The Impact

Dysregulation expression of miR-375 is noted to correlate with progression of cervical cancer. This study attempted to investigate the impact of overexpressed miR-375-loaded liposome nanoparticles on proliferation of cervical cancer (CC), to provide an insight on pathogenesis of CC disorder. CC cells were co-cultured with pure liposome nanoparticles (empty vector group), miR-375 agonist-loaded liposome nanoparticles, or transfected with miR-375 antagonist. Besides, some cells were exposed to TGF-β/Smads signaling pathway inhibitor or activator whilst cell proliferation was assessed by MTT assay, and expressions of FZD4 and miR-375 were determined. Western blot analysis was carried out to detect the expression of TGF-β pathway factors (TGF-β, Smad2, Smad7, p-Smad2) and its downstream Smads pathway. The interaction between miR-375 and FZD4 was evaluated by dual-luciferase reporter gene assay. Overexpression of miR-375 induced arrest at the G0/G1 phase of cell cycle and elevation of Smad2 protein expression (P <0.05), with lower expressions of TGF-β, Smad7, p-Smad2, and FZD4, while transfection with miR-375 inhibitor exhibited opposite activity. Presence of miR-375 agonist-loaded liposome nanoparticles induced decreased cell proliferation. There was a targeting relationship between miR-375 and FZD4, and administration with TGF-β/Smads agonist resulted in increased miR-375 and Smad2 expressions, as well as decreased TGF-β, Smad7, p-Smad2, FZD4 protein expression, and the number of S phase and G2/M phase cells (P < 0.05). The signaling inhibitor oppositely suppressed cell proliferation decreasing miR-375 expression. miR-375-loaded liposome nanoparticles activated TGF-β/Smads signaling pathway to restrain cell cycle and suppress cell division, and proliferation through targeting FZD4 in CC. Its molecular mechanism is related to activation of TGF-β/Smads signaling pathway.

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