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Inhibition of SLC1A 5 sensitizes colorectal cancer to cetuximab
Author(s) -
Ma Huanrong,
Wu Zhenzhen,
Peng Jianjun,
Li Yang,
Huang Hongxiang,
Liao Yi,
Zhou Minyu,
Sun Li,
Huang Na,
Shi Min,
Bin Jianping,
Liao Yulin,
Rao Jinjun,
Wang Lin,
Liao Wangjun
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31274
Subject(s) - cetuximab , colorectal cancer , gene silencing , cancer research , cancer , small hairpin rna , growth inhibition , medicine , pharmacology , chemistry , in vitro , biology , cell culture , gene , biochemistry , genetics , gene knockdown
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.