Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab.

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.

• Authors: Huanrong Ma, Zhenzhen Wu, Jianjun Peng, Yang Li, Hongxiang Huang, Yi Liao, Minyu Zhou, Li Sun, Na Huang, Min Shi, Jianping Bin, Yulin Liao, Jinjun Rao, Lin Wang, Wangjun Liao
• Journal: International journal of cancer (Int J Cancer) Vol. 142 Issue 12 Pg. 2578-2588 (06 15 2018) ISSN: 1097-0215 [Electronic] United States
• PMID: 29363109 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 UICC.

Chemical References

• Amino Acid Transport System ASC
• Antineoplastic Agents, Immunological
• Minor Histocompatibility Antigens
• SLC1A5 protein, human
• Cetuximab

Topics

• Amino Acid Transport System ASC (metabolism)
• Animals
• Antineoplastic Agents, Immunological
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cetuximab
• Colorectal Neoplasms (metabolism)
• Drug Resistance, Neoplasm (physiology)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Minor Histocompatibility Antigens (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays