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Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab
- Source :
- International Journal of Cancer. 142:2578-2588
- Publication Year :
- 2018
- Publisher :
- Wiley, 2018.
-
Abstract
- Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC.
- Subjects :
- 0301 basic medicine
Cancer Research
Cetuximab
Colorectal cancer
Cell growth
business.industry
medicine.disease
digestive system diseases
Solute carrier family
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Oncology
In vivo
Apoptosis
030220 oncology & carcinogenesis
Cancer cell
medicine
Cancer research
Gene silencing
business
neoplasms
medicine.drug
Subjects
Details
- ISSN :
- 00207136
- Volume :
- 142
- Database :
- OpenAIRE
- Journal :
- International Journal of Cancer
- Accession number :
- edsair.doi...........be5227dcb4334b45a34ca191d7dec732