Inhibition of metadherin sensitizes breast cancer cells to AZD6244

Abstract

The development of systemic therapy drug resistance for breast cancer treatment is an ongoing problem, thus, so are the potential molecular mechanisms of it. AZD6244 is a novel ATP-uncompetitive inhibitor to MAP/ERK kinase (MEK) 1/2 which has been demonstrated to be potent, selective and safe in the clinical trials and previous studies. However, the precise role of resistance to AZD6244 is largely unknown. We and other groups have reported that the novel oncogene Metadherin (MTDH) is associated with multiple drug resistance, but there is no report about its role in treatment of AZD6244. Here we report that the resistance to AZD6244 can be reserved by downregulating MTDH in breast cancer cell lines. When the MTDH was downregulated, the breast cancer cells exhibited a significantly increased sensitivity to AZD6244 as measured by MTT assay. After treated with AZD6244 the MTDH-knockdown cells showed more apoptosis rate and growth inhibition. We also showed that knockdown of MTDH cannot only increase expression of FOXO3a but also activate it by promoting its translocation via MTDH/ERK1/2/FOXO3a pathway rather than MTDH/AKT/FOXO3a pathway. In conclusion knockdown MTDH can enhance the breast cancer cells sensitivity to AZD6244 via regulating the expression and activity of FOXO3a. These indicate us that MTDH is a candidate marker to predict the clinical efficacy of AZD6244 and targeting MTDH could overcome the resistance to AZD6244 in breast cancer cells.

Metadherin, p50, and p65 Expression in Epithelial Ovarian Neoplasms: An Immunohistochemical Study

“…In line with our results in ovarian epithelial cancer, recently there has been emerging evidence from studies demonstrating a significant role for AEG-1/MTDH in the pathophysiology of several cancer types including breast cancer [9], large B-cell lymphoma [10], hepatocellular carcinoma, gastric cancer [11, 18], and prostate adenocarcinoma [15]. Furthermore, MTDH overexpression, inducing epithelial-mesenchymal transition, enhanced the migratory, and invasive properties of squamous head and neck cancer cells [12].…”

“…AEG-1/MTDH (astrocyte elevated gene-1 or metadherin or lyric), originally identified as a neuropathology-associated gene in primary human fetal astrocytes [7], is now established as an oncogene in a variety of cancers, including lung [8], breast [9], diffuse large B-cell lymphoma [10], hepatocellular carcinoma [11], squamous cell carcinoma of the head and neck [12], renal cell carcinoma [13], neuroblastoma [14], prostate cancer [15], glioma [16], colorectal cancer [17], and gastric cancer [18]. Human AEG-1/MTDH gene is located in chromosome 8q22 having 12 exons/11 introns.…”

Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review)

“…In summary, AEG-1/MTDH overexpression contributes to an aggressive phenotype, leading to a poor prognosis in primary invasive breast cancer. Blocking AEG-1/MTDH and its regulated pathways is likely to be beneficial in breast cancer cells or tissues (63,64). …”

The Role of AEG-1/MTDH/LYRIC in the Pathogenesis of Central Nervous System Disease

“…In a model of breast cancer, MTDH knockdown was shown to significantly enhance the cytotoxic effects of the potent oral inhibitor of MEK1/2 kinase, selumetinib (AZD6244), possibly through the release of FOXO3a from cytoplasmic proteasomal degradation (Kong, Moran, Zhao, & Yang, 2012). These results emphasize the regulation of protein stability by AEG-1/MTDH/LYRIC and highlight a potential activity that would be suitable for therapeutic intervention.…”