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Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1
- Publication Year :
- 2019
- Publisher :
- American Society for Clinical Investigation, 2019.
-
Abstract
- Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1(–/–) Trp53(–/–) SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin β1, which stabilized integrin β1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin β1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.
- Subjects :
- 0301 basic medicine
Male
Lung Neoplasms
Integrin
Mice, Nude
Metastasis
Focal adhesion
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Animals
Humans
SOCS3
Neoplasm Metastasis
Mice, Knockout
Mice, Inbred BALB C
biology
business.industry
Protein Stability
Integrin beta1
Cancer
General Medicine
Neoplasms, Experimental
medicine.disease
Cullin Proteins
Small Cell Lung Carcinoma
Ubiquitin ligase
respiratory tract diseases
Neoplasm Proteins
Dasatinib
030104 developmental biology
HEK293 Cells
030220 oncology & carcinogenesis
biology.protein
Cancer research
business
medicine.drug
Proto-oncogene tyrosine-protein kinase Src
Research Article
HeLa Cells
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....bb1d96040e60660bdc60d064663e54cd