RESUMEN
Background Recent studies have shown that the activation of PI3K/AKT signaling pathway is an essential molecular mechanism participating in trastuzumab resistance in HER2 + GC (gastric cancer). However, how can we effectively inhibit AKT activity associated with drug resistance during trastuzumab treatment? Screening inhibitors against the upstream receptors of PI3K/AKT signaling pathway or interacting proteins of members has become an important way. Methods In this study, western blot, qRT-PCR, CCK8, Co-IP and other techniques were used to explore possible mechanisms participating in trastuzumab resistance in vitro. Besides, the xenograft mouse model and GC tissue samples from patients were used to further validate the in-vitro results. Results The expression of XB130 adaptor protein was remarkably increased in GC cell lines resistant to trastuzumab, and knockdown of XB130 could reverse the resistance via downregulating p-AKT. In addition, p-SRC (Tyr416) was increased in resistant cells, which could facilitate the binding of XB130 to PI3K p85α. It was also discovered that XB130 could negatively regulate PTEN gene transcription, and thus a positive feedback loop was formed between SRC-XB130-PTEN. Conclusions In HER2 + GC, XB130 contributes to trastuzumab resistance by stimulating the PI3K/AKT signaling pathway through binding to PI3K p85α under the mediation of SRC kinase and regulating PTEN gene transcription, and in turn forming a positive feedback loop between SRC-XB130-PTEN (AU)
Asunto(s)
Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas , Trastuzumab/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Fosfohidrolasa PTEN , Transducción de Señal , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
BACKGROUND: Recent studies have shown that the activation of PI3K/AKT signaling pathway is an essential molecular mechanism participating in trastuzumab resistance in HER2 + GC (gastric cancer). However, how can we effectively inhibit AKT activity associated with drug resistance during trastuzumab treatment? Screening inhibitors against the upstream receptors of PI3K/AKT signaling pathway or interacting proteins of members has become an important way. METHODS: In this study, western blot, qRT-PCR, CCK8, Co-IP and other techniques were used to explore possible mechanisms participating in trastuzumab resistance in vitro. Besides, the xenograft mouse model and GC tissue samples from patients were used to further validate the in-vitro results. RESULTS: The expression of XB130 adaptor protein was remarkably increased in GC cell lines resistant to trastuzumab, and knockdown of XB130 could reverse the resistance via downregulating p-AKT. In addition, p-SRC (Tyr416) was increased in resistant cells, which could facilitate the binding of XB130 to PI3K p85α. It was also discovered that XB130 could negatively regulate PTEN gene transcription, and thus a positive feedback loop was formed between SRC-XB130-PTEN. CONCLUSIONS: In HER2 + GC, XB130 contributes to trastuzumab resistance by stimulating the PI3K/AKT signaling pathway through binding to PI3K p85α under the mediation of SRC kinase and regulating PTEN gene transcription, and in turn forming a positive feedback loop between SRC-XB130-PTEN.
Asunto(s)
Proteínas Proto-Oncogénicas c-akt , Neoplasias Gástricas , Humanos , Animales , Ratones , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos , Fosfohidrolasa PTENRESUMEN
Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.
