Oncotarget

Research Papers:

RACK1 overexpression is linked to acquired imatinib resistance in gastrointestinal stromal tumor

Xiaodong Gao, Anwei Xue, Yong Fang, Ping Shu, Jiaqian Ling, Yingyong Hou, Kuntang Shen _, Jing Qin, Yihong Sun and Xinyu Qin

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Oncotarget. 2016; 7:14300-14309. https://doi.org/10.18632/oncotarget.7426

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Abstract

Xiaodong Gao1,2, Anwei Xue1,2, Yong Fang1,2, Ping Shu1,2, Jiaqian Ling1,2, Yingyong Hou3, Kuntang Shen1,2, Jing Qin1,2, Yihong Sun1,2 and Xinyu Qin1,2

1 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

2 Institute of General Surgery, Fudan University, Shanghai, China

3 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China

Correspondence to:

Kuntang Shen, email:

Yingyong Hou, email:

Keywords: gastrointestinal stromal tumor, KIT, RACK1, imatinib

Received: November 04, 2015 Accepted: January 29, 2016 Published: February 16, 2016

Abstract

Although treatment with imatinib, which inhibits KIT and PDGFR, controls advanced disease in about 80% of gastrointestinal stromal tumor (GIST) patients, resistance to imatinib often develops. RACK1 (Receptor for Activated C Kinase 1) is a ribosomal protein that contributes to tumor progression by affecting proliferation, apoptosis, angiogenesis, and migration. Here, we found that c-KIT binds to RACK1 and increases proteasome-mediated RACK1 degradation. Imatinib treatment inhibits c-KIT activity and prevents RACK1 degradation, and RACK1 is upregulated in imatinib-resistant GIST cells compared to non-resistant parental cells. Moreover, Erk and Akt signaling were reactivated by imatinib in resistant GIST cells. RACK1 functioned as a scaffold protein and mediated Erk and Akt reactivation after imatinib treatment, thereby promoting GIST cell survival even in the presence of imatinib. Combined inhibition of KIT and RACK1 inhibited growth in imatinib-resistant GIST cell lines and reduced tumor relapse in GIST xenografts. These findings provide new insight into the role of RACK1 in imatinib resistance in GIST.


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