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.

Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk

“…Our previous studies have demonstrated that catecholamines stimulate STAT3 activation in breast (Shi et al 2011) and gastric cancer cells (Shi et al 2010(Shi et al , 2013b. Results shown in Fig.…”

“…Amplification of b-actin (with the primers listed in Supplementary Table S1) was used as the control. The expressions of Jagged 1 and b-actin in MDA-231, MDA-453, 4T1, and MCF-7 cells were detected by real-time RT-PCR (with the primers listed in Supplementary Table S1) as described in our previous study (Shi et al 2013b). The experiments were performed three times independently.…”

Unique Cellular Lineage Composition of the First Gland of the Mouse Gastric Corpus

“…[35][36][37] Previous studies have indicated expression of MUC4 in both gastric tumors and Barrett's esophagus. 36,[38][39][40] MUC4 is upregulated in SPEM in rodent models.…”

Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases

“…It is reported that two single nucleotide polymorphisms (rs4072037 and rs2070803) in the MUC1 gene has been identified in gastric cancer patients and may have a prospective role in the stratification of high-risk subjects [171]. The overexpression of MUC1 and MUC4 also mediates resistance to the trastuzumab, a monoclonal antibody against HER-2/neu [172,173] siRNA to MUC1 was tested in trastuzumab drug resistance cells and a better response to the drug was seen in siRNA treated drug resistant cell when compared to control or junk siRNA treatment [174].…”

“…Therefore, in cancer transformations, during progression and even in drug response mucin molecule plays an important role [47] thus considered as diagnostic marker [33] and drug target for cancer detection and therapies [48]. Functional analysis of drug resistant cancer cells revealed the differential expression of mucin potentially involved in angiogenesis, metastasis, differentiation and proliferation [49,50]. Abnormal expression of the mucins are said to be reported in various cancers [51,52], such as pancreatic adenocarcinomas, colon carcinomas [53], Breast cancer [48,54] and cancers associated with other organs (Fig.…”