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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells
Hong Yuan1,2, Zi-Ming Li1, Jiaxiang Shao2
1Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
Background:
Autophagy is a conserved catabolic process to degrade cellular organelles. The role of autophagy in cancer development is complex. Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC). Whether fibroblast growth factor 2 (FGF2)/FGFR1 contributes to the regulation of autophagy remains elusive.
Methods:
Autophagic activity was evaluated by immunoblotting for microtubule-associated protein 1 light chain 3 (LC3), formation of GFP-LC3 puncta, and monodansylcadaverine (MDC) staining. The effect of autophagy inhibition on cell survival was assessed by cell viability and apoptosis assays.
Results:
We elucidated that FGFR1 activation suppressed autophagy. Pharmacological or genetic inhibition of FGFR1 by AZD4547 or FGFR1 short hairpin RNA (shRNA) induced autophagy in FGFR1-amplified non-small cell lung cancer (NSCLC) cells, H1581 and H520 cells. Mechanistic study revealed that the induction of autophagy by FGFR1 inhibition was mediated through inhibiting the ERK/MAPK pathway not by AKT pathway, accompanied by upregulation of beclin-1. Furthermore, activation of ERK/MAPK by transfection with a constitutively active MEK1 (caMEK1) construct or knockdown of beclin-1 by RNAi could attenuate autophagy induced by FGFR1 inhibition. Beclin-1 expression was inversely correlated with MEK1 phosphorylation. Inhibition of autophagy by beclin-1 silencing could enhance apoptosis after AZD4547 treatment in H1581 and H520 cells. High levels of LC3B mRNA was a marker of poor prognosis in NSCLC patients.
Conclusions:
Simultaneously inhibiting FGFR1 and autophagy could enhance cell death which should be further explored in vivo.
Insights
Fibroblast growth factor receptor 1 (FGFR1) activation suppresses autophagy in lung cancer. Inhibiting FGFR1 or the ERK/MAPK pathway induces autophagy, enhancing cell death when combined with autophagy inhibition.
Area of Science:
- Cellular Biology
- Cancer Research
- Molecular Oncology
Background:
- Autophagy, a cellular degradation process, has a complex role in cancer development.
- Fibroblast growth factor receptor 1 (FGFR1) amplification is common in lung squamous cell carcinoma (SQCC).
- The specific role of fibroblast growth factor 2 (FGF2)/FGFR1 in regulating autophagy remains unclear.
Purpose of the Study:
- To investigate the role of FGF2/FGFR1 signaling in autophagy regulation within lung cancer.
- To determine the therapeutic potential of targeting FGFR1 and autophagy concurrently in non-small cell lung cancer (NSCLC).
Main Methods:
- Autophagic activity assessed via LC3 immunoblotting, GFP-LC3 puncta, and monodansylcadaverine (MDC) staining.
- Cell viability and apoptosis assays evaluated the impact of autophagy inhibition.
- Pharmacological (AZD4547) and genetic (shRNA) inhibition of FGFR1 were employed.
Main Results:
- FGFR1 activation was found to suppress autophagy.
- Inhibition of FGFR1 (pharmacologically or genetically) induced autophagy in NSCLC cells.
- Autophagy induction by FGFR1 inhibition was mediated by the ERK/MAPK pathway, not AKT, and involved beclin-1 upregulation.
- Combined inhibition of FGFR1 and autophagy enhanced cancer cell apoptosis.
Conclusions:
- Simultaneous inhibition of FGFR1 and autophagy presents a promising therapeutic strategy for enhancing cancer cell death.
- Further in vivo studies are warranted to validate these findings.
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