Molecular Mechanism of Chemoresistance by Astrocyte Elevated Gene-1

Yoo, Byoung Kwon; Chen, Dong; Su, Zhao-zhong; Gredler, Rachel; Yoo, Jinsang; Shah, Khalid; Fisher, Paul B.; Sarkar, Devanand

doi:10.1158/0008-5472.can-09-4009

Cited by 106 publications

(148 citation statements)

References 40 publications

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“…Alternatively, SND1 has also been shown to be involved in RNA-induced silencing complex activity and degradation of edited double-stranded RNA molecules. Furthermore, MTDH was reported to post-transcriptionally regulate translation of the multidrug resistance protein 1 (MDR1) (11). Therefore, cytoplasmic interactions between MTDH and SND1 may regulate RNA silencing and/or editing machinery to modulate RNA stability, translation, or functionality.…”

Section: Discussionmentioning

confidence: 99%

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

Blanco

Alečković

Hua

et al. 2011

Journal of Biological Chemistry

110

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Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis.Metastasis is responsible for the majority of cancer-related deaths (1). An increasing number of genes have been implicated in mediating different steps of metastasis, but relatively few are mechanistically well characterized (2). One recently verified mediator of distant metastasis is Metadherin (MTDH 3 ; also called Lyric and AEG1 (3-5)). MTDH has been shown to be a key functional target of the 8q22 genomic gain that is frequently observed in poor prognosis breast cancer patients (6). Beyond promoting experimental lung metastasis (3, 6), multiple studies have implicated MTDH as a mediator of several cancer-related processes, such as oncogenesis and angiogenesis (7,8), invasion (9), chemoresistance (6, 10 -12), apoptosis resistance (13), and autophagy (14). Despite the abundance of MTDH phenotypes, a consensus understanding of its underlying molecular mechanisms has not yet been reached. MTDH has been shown to influence several oncogenic signaling pathways and transcription factors, such as Ha-Ras (15), PI3K/AKT (13), ERK, Wnt/␤-catenin (8), NF-B (16), c-Myc (15), and FOXO1/FOXO3a (17, 18). However, MTDH regulation of signaling pathways appears to be context-dependent with affected pathways varying by tumor type and cell line (19,20). Furthermore, prior work on MTDH molecular mechanisms has largely focused on hypothesis-driven investigations into the ability of MTDH to influence classical oncogenic pathways with little exploration to date on protein-level interactions (16,21).In this study, we aimed to expand the knowledge of MTDH molecular functionality and also uncover novel genes involved in promoting distant metastasis. Our approach utilized an unbiased, mass spectrometry-based screen for MTDH-interacting partners. We identified and characterized the interaction between MTDH and one such protein, SND1. SND1 is a multifunctional protein with reported roles in transcriptional activation (22), RNA editing (23, 24), formation of the RNAinduced ...

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Section: Discussionmentioning

confidence: 99%

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

Blanco

Alečković

Hua

et al. 2011

Journal of Biological Chemistry

110

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“…Recent studies have documented that AEG-1 contributes to broadspectrum resistance to various chemotherapeutics including 5-fluorouracil (5-Fu), doxorubicin, paclitaxel, cisplatin and 4-hydroxycyclophosphamide (4-HC) (16,21,(55)(56)(57). Hepatocytes isolated from Alb/AEG-1 mice also displayed profound resistance to chemotherapeutics (49).…”

Section: Aeg-1 Promotes the Chemoresistance Of Hccmentioning

confidence: 99%

The emerging role of astrocyte-elevated gene-1 in hepatocellular carcinoma (Review)

Zhu

Liao

et al. 2015

Oncology Reports

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Abstract. Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, yet effective treatment for this disease is lacking. Thus, there is an urgent need to identify novel therapeutic targets for this dreadful disease. Numerous studies have established that overexpression of astrocyteelevated gene-1 (AEG-1) is frequently observed in multiple types of cancers including HCC, and its expression levels are correlated with the stage and grade of the disease. Further studies revealed that AEG-1 plays a key role in several crucial aspects of HCC progression, including growth, transformation, cell survival, invasion, metastasis and chemoresistance. Moreover, AEG-1 overexpression activates the Wnt/β-catenin, mitogen-actived protein kinase (MAPK), nuclear factor (NF)-κB, and PI3K/Akt signaling pathways, and promotes its downstream gene expression to facilitate malignant potential. Recently, transgenic mice with hepatocyte-specific expression of AEG-1 (Alb/AEG-1) and AEG-1-knockout mouse both revealed novel aspects of the functions of AEG-1 in an in vivo context. This review evaluates the multi-functions of AEG-1 and describes the major signaling pathways and molecular alterations regulated by AEG-1 in HCC, indicating its key roles and potential as a biomarker or significant target for the therapy of HCC.

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“…In addition, AEG-1 enhanced the expression of dihydropyrimidine dehydrogenase (DPYD), which catalyzes the initial and rate-limiting step in the catabolism of 5-FU (42). A recent study reported a new mechanism through which AEG-1 plays a role in chemoresistance in human HCC (43). AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein, resulting in increased efflux and decreased accumulation of doxorubicin, thereby promoting doxorubicin resistance (43).…”

Section: Aeg-1 and Chemoresistance Of Breast Cancermentioning

confidence: 99%

“…A recent study reported a new mechanism through which AEG-1 plays a role in chemoresistance in human HCC (43). AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein, resulting in increased efflux and decreased accumulation of doxorubicin, thereby promoting doxorubicin resistance (43). AEG-1 increases the expression of MDR1 by facilitating the association of MDR1 mRNA to polysomes, resulting in increased translation.…”

Section: Aeg-1 and Chemoresistance Of Breast Cancermentioning

confidence: 99%

“…AEG-1 increases the expression of MDR1 by facilitating the association of MDR1 mRNA to polysomes, resulting in increased translation. AEG-1 also inhibits ubiquitination and subsequent proteasome-mediated degradation of the MDR1 protein (43). In neuroblastoma cells, a significant enhancement in chemosensitivity to cisplatin and doxorubicin by knockdown of AEG-1 was observed (40).…”

Section: Aeg-1 and Chemoresistance Of Breast Cancermentioning

confidence: 99%

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Astrocyte elevated gene-1 and breast cancer (Review)

Wang

Yang

2011

Oncology Letters

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Abstract. Astrocyte elevated gene-1 (AEG-1), also known as MTDH and Lyric, is a novel gene that was first cloned by subtraction hybridization in 2002 and has recently been shown to play a role as a crucial oncogene that acts as a promoter of tumor malignancy. Overexpression and inhibition studies both in in vitro and in vivo models have partly shown the oncogenic roles of AEG-1 in a number of crucial aspects of tumor development and progression, including transformation, evasion of apoptosis, proliferation, cell survival, migration, invasion, metastasis, angiogenesis and chemoresistance through the activation of numerous signaling pathways, such as the nuclear factor κB, PI3K/AKT, Wnt/β-catenin and mitogen-activated protein kinase signaling pathways. However the potential roles of AEG-1, particularly in specific organs or tissues, such as breast tissue, require further clarification. Studies have found that in normal human breast tissue, AEG-1 is always expressed at low levels or is absent, while it is widely overexpressed in many breast cancer cell lines and breast tumors. The present review evaluates the current literature with regards to AEG-1 relative to breast cancer development and progression and highlights new perspectives relative to this molecule, indicating its potential to become a new target for the clinical treatment of breast cancer.

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Molecular Mechanism of Chemoresistance by Astrocyte Elevated Gene-1

Cited by 106 publications

References 40 publications

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

The emerging role of astrocyte-elevated gene-1 in hepatocellular carcinoma (Review)

Astrocyte elevated gene-1 and breast cancer (Review)

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