Glioblastoma Proto-oncogene SEC61γ Is Required for Tumor Cell Survival and Response to Endoplasmic Reticulum Stress

Abstract

Glioblastoma multiforme is the most prevalent type of adult brain tumor and one of the deadliest tumors known to mankind. The genetic understanding of glioblastoma multiforme is, however, limited, and the molecular mechanisms that facilitate glioblastoma multiforme cell survival and growth within the tumor microenvironment are largely unknown. We applied digital karyotyping and single nucleotide polymorphism arrays to screen for copy-number changes in glioblastoma multiforme samples and found that the most frequently amplified region is at chromosome 7p11.2. The high resolution of digital karyotyping and single nucleotide polymorphism arrays permits the precise delineation of amplicon boundaries and has enabled identification of the minimal region of amplification at chromosome 7p11.2, which contains two genes, EGFR and SEC61γ. SEC61γ encodes a subunit of a heterotrimeric protein channel located in the endoplasmic reticulum (ER). In addition to its high frequency of gene amplification in glioblastoma multiforme, SEC61γ is also remarkably overexpressed in 77% of glioblastoma multiforme but not in lower-grade gliomas. The small interfering RNA-mediated knockdown of SEC61γ expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacologic ER stress agents induce SEC61γ expression in glioblastoma multiforme cells. Together, these results indicate that aberrant expression of SEC61γ serves significant roles in glioblastoma multiforme cell survival likely via a mechanism that is involved in the cytoprotective ER stress-adaptive response to the tumor microenvironment. [Cancer Res 2009;69(23):9105-11]

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game

“…Separately, the validated hit SEC61G, which is part of a protein translocation complex in the endoplasmic reticulum (ER) membrane, may affect poliovirus replication by altering ER-Golgi complex protein translocation. Such changes could result in (i) accumulation of membrane structures used for poliovirus RNA replication, (ii) enhancement of virus release, and/or (iii) viral evasion of host immune responses (19,(32)(33)(34). As enterovirus replication requires the accumulation of phosphatidylinositol-4-phosphate (PI4P) lipids and unesterified cholesterol on membrane structures (35,36), the possible role for the BTN2A1 gene discovered in this study is becoming clearer due to its known involvement in lipid metabolism.…”

“…EP300, as well as GLRXP3 and CNTD2, has also been shown to be related to the NF-B transcriptional response, regulating cell survival and innate immune responses (16). At least six genes, ETS1, GLRXP3, EP300, GCGR, SEC61g, and ZNF205, are associated with cell death/apoptosis (17)(18)(19).…”

Integrated Proteomic and Transcriptomic-Based Approaches to Identifying Signature Biomarkers and Pathways for Elucidation of Daoy and UW228 Subtypes

“…Interestingly, the set of genes amplified in Daoy, relative to UW228, included a number of genes located on chromosome 7 ( EGFR , LANCL2 ) and 17 ( CRK , TP53 , GRB2 , TOP2A , JUP ). Gains in chromosome 7p11 [58] and chromosome 17p13, a region with a high incidence of loss of heterozygosity [59], have been reported in various cancers [60]. This may explain the high expression levels of genes located on both chromosomal regions in Daoy, which may correlate with its greater rate of cell division and migration and more invasive growth phenotype.…”

Isolation and Characterization of an Huh.7.5.1-Derived Cell Clone Highly Permissive to Hepatitis C Virus

“…Girard et al previously showed that NTS is highly upregulated in HCV NS5A-expressing Huh7 cells (37) and may be associated with efficient HCV replication. The genes NTS and AFP are also known to be upregulated in hepatic tumors (38,39), and the protein SEC61G is required for tumor cell survival (40). In addition, AGR2 acts as a p53 tumor suppressor inhibitor (41).…”