Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

Abstract

Background/Aim: The resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, is considered a major challenge in the treatment of patients with non-small cell lung cancer (NSCLC). Herein, we identified the critical roles of anterior gradient 2 (AGR2) in gefitinib (Gef) resistance of mutant NSCLC cells. Materials and Methods: Using datasets from a pair of NSCLCsensitive and NSCLC-resistant cells, immunoblotting, immunofluorescence and immunohistochemistry, and cell viability assays were applied to identify the effects of AGR2. Results: AGR2 was found to be significantly over-expressed in Gef-resistant cells and was highly associated with drug resistance, proliferation, migration, and invasion of cancer cells. Moreover, AGR2 and ADAMTS6 formed a negative feedback loop in drug-resistant cells. Conclusion: Modulation of overexpression of AGR2 in mutant NSCLC cells may be an attractive therapeutic strategy for the treatment of EGFR-TKI-resistant NSCLC. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related death worldwide, and comprises 85% of all lung cancer cases (1). Acquired drug resistance in tumor cells is a major obstacle in the field of anti-cancer chemotherapies. Likewise, NSCLC patients who initially show a good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib (Gef), acquire resistance to treatment (2). However, studies on the mechanisms through which overexpression of specific genes is involved in EGFR-TKI resistanse of NSCLC cells are scarce and its role remains to be elucidated. Therefore, novel approaches are required to elucidate their role in drug resistanse of cancer cells. The anterior gradient-2 (AGR2) has been identified in Xenopus laevis and plays a critical role in cemet gland differentiation (3). Recent studies have suggested that elevated expression of AGR2 is correlated with cell proliferation, metastasis, and drug resistance in various human cancer cell lines, such as prostate (4), breast (5), and pancreatic cancer (6). Moreover, overexpression of AGR2 has been notably correlated with a poor outcome of estrogen receptor-negative breast cancer patients (7). AGR2 is also a pro-oncogenic protein that has been shown to stimulate the epidermal growth factor receptor (EGFR) ligand amphiregulin, regulate p53 signaling, and interact with the AAA+ protein Reptin (8), suggesting its modulatory roles in gene expression. High expression of AGR2 has also been shown to be predictive of poor survival in lung cancer (9). However, there is still a lack of insightful understanding of the role of AGR2 in EGFR-TKI-resistant NSCLC cells. There are 19 members of zinc-dependent metalloproteases in the family of a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) (10). Recent reports suggest the critical roles of ADAMTSs in angiogenesis and cancer (11). They also play an important role in the modulation of extracellular matrix. For instance, ADAMTS-1 metallopro...

Yuanhuacin and Related Anti-Inflammatory and Anticancer Daphnane Diterpenes from Genkwa Flos—An Overview

“…The anticancer activity of YD toward EGFR-TKI-resistant cells and tumors is particularly interesting and has boosted a number of studies to define the molecular factors implicated in the activity of the compound. Lee and coworkers have identified several key factors playing a role in the restoration of EGFR-TKIs sensitivity, such as (i) the metabolic enzyme nicotinamide N-methyltransferase (NNMT) which expression is suppressed by YD in EGFR-TKI-resistant NSCLC cells [ 75 ], (ii) the bone morphogenetic protein BMP4 which expression is also drastically reduced in the same cells upon treatment with YD [ 76 ] and recently (iii) the anterior gradient protein 2 (AGR2) which is considered a marker of tumor aggressiveness, downregulated by YD in NSCLC-resistant cells [ 77 ]. YD also displays anti-inflammatory effects, reducing the production of nitric oxide (NO) in LPS-activated microglial BV2 cells with an efficacy comparable to that of YT [ 21 ].…”

Porous Silicon-Based Aptasensors: Toward Cancer Protein Biomarker Detection

“…The detection of protein biomarkers in body fluids for the diagnosis and prognosis of various diseases enables the development of minimally invasive and point-of-care assays. For example, screening of protein biomarkers for various types of cancer is highly valuable for cancer management and monitoring. ,, Increasing interest has been devoted toward the protein anterior gradient homologue-2 (AGR2) over the past decade due to its diagnostic and prognostic value for pancreatic, breast, ovarian, prostate, and colorectal cancer. − Specifically in pancreatic cancer, which is one of the most lethal types of cancer, AGR2 has been suggested to play an important role in cancer initiation and development. Moreover, the level of AGR2 has been found to be elevated, at a concentration in the subnanomolar range, in the pancreatic juice of patients with high-grade pancreatic intraepithelial neoplastic lesions, which are precursors to invasive pancreatic cancer. − This would be an ideal stage for diagnosis, as it is a time point when surgical resection can potentially prevent the progression to malignancy .…”

Hypomethylation-Mediated AGR2 Overexpression Facilitates Cell Proliferation, Migration, and Invasion of Lung Adenocarcinoma

“… 16 In addition, AGR2 is highly expressed in esophageal cancer, 17 pancreatic cancer, 18 prostate cancer, 19 and lung cancer. 20 , 21 ARG2 is thought to promote proliferation, survival, and metastasis of tumor cells. Salmans et al demonstrated that AGR2 is a marker of breast cancer metastasis, and its overexpression in estrogen receptor-positive breast cancer is associated with poor prognosis, especially in tumors that evade anti-hormone therapy, 22 suggesting that AGR2 may be involved in cell metastasis in hormone-related tumors.…”