title: Catecholamine-Induced β2-adrenergic receptor activation mediates desensitization of gastric cancer cells to trastuzumab by upregulating MUC4 expression.
abstract: Trastuzumab is currently used for patients with Her2(+) advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of β2-adrenergic receptor (β2-AR) triggered by catecholamine caused "targeting failure" of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by β2-AR antagonist ICI-118,551, indicating that β2-AR-mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of β2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine-induced β2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression.
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
authors: Ming
authors: M
authors: Shi
authors: Zhengyan
authors: Z
authors: Yang
authors: Meiru
authors: M
authors: Hu
authors: Dan
authors: D
authors: Liu
authors: Yabin
authors: Y
authors: Hu
authors: Lu
authors: L
authors: Qian
authors: Wei
authors: W
authors: Zhang
authors: Hongyu
authors: H
authors: Chen
authors: Liang
authors: L
authors: Guo
authors: Ming
authors: M
authors: Yu
authors: Lun
authors: L
authors: Song
authors: Yuanfang
authors: Y
authors: Ma
authors: Ning
authors: N
authors: Guo
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D055264:Mucin-4 / Q000235:genetics*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002395:Catecholamines; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol; D055264:Mucin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D018343:Receptors, Adrenergic, beta-2; D050796:STAT3 Transcription Factor; D000068878:Trastuzumab