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Glioblastoma proto-oncogene SEC61gamma 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 SEC61gamma. SEC61gamma 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, SEC61gamma is also remarkably overexpressed in 77% of glioblastoma multiforme but not in lower-grade gliomas. The small interfering RNA-mediated knockdown of SEC61gamma expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacologic ER stress agents induce SEC61gamma expression in glioblastoma multiforme cells. Together, these results indicate that aberrant expression of SEC61gamma 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.

SUBMITTER: Lu Z

PROVIDER: S-EPMC2789175 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress.

Lu Zheming Z Zhou Lei L Killela Patrick P Rasheed Ahmed B AB Di Chunhui C Poe William E WE McLendon Roger E RE Bigner Darell D DD Nicchitta Christopher C Yan Hai H

Cancer research 20091117 23

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 th ...[more]

PMID: 19920201

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Project description:Background Glioblastoma (GBM; grade IV glioma) is characterized by a very short overall survival time and extremely low 5-year survival rates. We intend to promote experimental and clinical research on rationale and scientifically driven drug repurposing. This may represent a safe and often inexpensive way to propose novel pharmacological approaches to GBM. Our precedent work describes the role of chlorpromazine (CPZ) in hindering malignant features of GBM. Here, we investigate in greater detail the molecular mechanisms at the basis of the effect of CPZ on GBM cells. Methods We employed proteomics platforms, i.e., activity-based protein profiling plus mass spectrometry, to identify potential cellular targets of the drug. Then, by means of established molecular and cellular biology techniques, we assessed the effects of this drug on GBM cell metabolic and survival pathways. Results The experimental output indicated as putative targets of CPZ several of factors implicated in endoplasmic reticulum (ER) stress, with consequent unfolded protein response (UPR). Such a perturbation culminated in a noticeable reactive oxygen species generation and intense autophagic response that resulted in cytotoxic and abortive effects for six GBM cell lines, three of which growing as neurospheres, while it appeared cytoprotective for the RPE-1 human non-cancer neuro-ectodermal cell line. Conclusions This discrepancy could be central in explaining the lethal effects of the drug on GBM cells and the relatively scarce cytotoxicity toward normal tissues attributed to this compound. The data presented here offer support to the multicenter phase II clinical trial we have undertaken, which consists of the addition of CPZ to first-line treatment of GBM patients carrying a hypo- or un-methylated MGMT gene, i.e. those characterized by intrinsic resistance to temozolomide. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02144-w.

Dataset Information

Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress.

Publications

Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress.

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