Y-box Binding Protein-1 Contributes to Both HER2/ErbB2 Expression and Lapatinib Sensitivity in Human Gastric Cancer Cells

Shibata, Tomohiro; Kan, Hitoshi; Murakami, Yûichi; Ureshino, Hiroki; Watari, Kosuke; Kawahara, Akihiko; Kage, Masayoshi; Hattori, Satoshi; Ono, Masahiro; Kuwano, Michihiko

doi:10.1158/1535-7163.mct-12-1125

Cited by 31 publications

(21 citation statements)

References 41 publications

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“…Tomohiro Shibata et al reported that silencing of YB-1 specifically down-regulates HER2 expression and induces lapatinib resistance in GC cells [26]. The data presented here indicated that sensitivity of lapatinib altered by JWA was dependent on HER2 expression.…”

Section: Discussionsupporting

confidence: 52%

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

Zhu

Wang

et al. 2016

Oncotarget

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Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells. Whereas, deletion of JWA significantly restored lapatinib suppression on proliferation and lapatinib-induced apoptosis. JWA-induced down-regulation of HER2 and activation of ERK phosphorylation led to lapatinib resistance. Furthermore, c-Cbl represented a novel mechanism for HER2 degradation enhanced by JWA in GC cells. Taken together, JWA is a potential predictive marker for lapatinib resistance, targeting the patients that may benefit from lapatinib treatment in human GC.

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Section: Discussionsupporting

confidence: 52%

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

Zhu

Wang

et al. 2016

Oncotarget

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“…Furthermore, afatinib-resistant sublclones are also cross-resistant to gefitinib and also lapatinib (Table 1). EGFR forms a duplex with HER2 or HER3 (31), and sensitivity to lapatinib is controlled through HER2 and/or EGFR (32, 33). The cross-resistance to lapatinib in afatinib-resistant sublclones might be due to marked downregulation of HER2/pHER2 and pEGFR/activated mutant EGFR.…”

Section: Discussionmentioning

confidence: 99%

FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor

et al. 2014

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Most NSCLC patients with EGFR mutations benefit from treatment with EGFR-TKIs, but the clinical efficacy of EGFR-TKIs is limited by the appearance of drug resistance. Multiple kinase inhibitors of EGFR family proteins such as afatinib have been newly developed to overcome such drug resistance. We established afatinib-resistant cell lines after chronic exposure of activating EGFR mutation-positive PC9 cells to afatinib. Afatinib-resistant cells showed following specific characteristics as compared to PC9: [1] Expression of EGFR family proteins and their phosphorylated molecules was markedly downregulated by selection of afatinib resistance; [2] Expression of FGFR1 and its ligand FGF2 was alternatively upregulated; [3] Treatment with anti-FGF2 neutralizing antibody blocked enhanced phosphorylation of FGFR in resistant clone; [4] Both resistant clones showed collateral sensitivity to PD173074, a small-molecule FGFR-TKIs, and treatment with either PD173074 or FGFR siRNA exacerbated suppression of both afatinib-resistant Akt and Erk phosphorylation when combined with afatinib; [5] Expression of twist was markedly augmented in resistant sublines, and twist knockdown specifically suppressed FGFR expression and cell survival. Together, enhanced expression of FGFR1 and FGF2 thus plays as an escape mechanism for cell survival of afatinib-resistant cancer cells, that may compensate the loss of EGFR-driven signaling pathway.

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“…The extent of p-EGFR staining was evaluated according to the percentage of cells with strongly stained nuclei in 3 visual fields under a light microscope (x200). All immunohistochemistry studies were evaluated by 2 experienced observers who were blind to the conditions of the experiments as reported previously (35).…”

Section: Immunohistochemistry For Xenograft Tumor Specimensmentioning

confidence: 99%

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

et al. 2018

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Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p-EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non-neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti-cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine-nAChR signaling to metastasize and acquire resistance to anti-cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti-EGFR-therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p-EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab-inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p-EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p-EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.

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Y-box Binding Protein-1 Contributes to Both HER2/ErbB2 Expression and Lapatinib Sensitivity in Human Gastric Cancer Cells

Cited by 31 publications

References 41 publications

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

JWA down-regulates HER2 expression via c-Cbl and induces lapatinib resistance in human gastric cancer cells

FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

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