Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012:2012:838916.
doi: 10.1100/2012/838916. Epub 2012 Feb 14.

The role of Bcl-2 family proteins in therapy responses of malignant astrocytic gliomas: Bcl2L12 and beyond

Fotini M Kouri  1 , Samuel A Jensen, Alexander H Stegh
Affiliations
Review

The role of Bcl-2 family proteins in therapy responses of malignant astrocytic gliomas: Bcl2L12 and beyond

Fotini M Kouri et al. ScientificWorldJournal. 2012.

Abstract

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ) in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs), revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12), as important regulators of therapy-induced cell death. This review will discuss the multi-faceted modi operandi of Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The Bcl-2 family. Domain structure of mammalian, viral, and C. elegans proteins. Shown are antiapoptotic “core” proteins, atypical Bcl-2-like proteins, for example, Bcl2L12 and Bcl2L13, proapoptotic multidomain, and BH3-only proteins. Bcl2L12 is characterized by six PxxP motifs located in the N-terminal and center portion of the molecule; these PxxP motifs are depicted as dark red boxes. BH: Bcl-2 homology domain; BHNo: no BH domain; TM: transmembrane domain. Bcl-2: B-cell lymphoma-2; Mcl-1: myeloid cell leukemia sequence 1 (Bcl-2-related); Bim: Bcl-2-interacting mediator of cell death; Bad: Bcl-xL/Bcl-2-associated death promoter; Bid: Bcl-2-interacting domain; Puma: p53 upregulated mediator of apoptosis; Bik: Bcl-2-interacting killer; Bmf: Bcl-2-modifying factor; Hrk: Harakiri; Bcl2Lxx: Bcl-2-Like xx; Bok: Bcl-2-related ovarian killer protein; ORF: open reading frame; Bax: Bcl-2-associated X protein; Bak: Bcl-2-antagonist/killer 1; CED-9: cell death abnormality family member; Bnip3: Bcl-2/adenovirus E1B 19 kDa interacting protein 3; Egl-1: egg laying abnormal-1; Mule: Mcl-1 ubiquitin ligase E3. Size of proteins is only approximate.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. Journal of Neuropathology and Experimental Neurology. 2002;61(3):215–225. - PubMed
    1. Wen PY, Kesari S. Malignant gliomas in adults. The New England Journal of Medicine. 2008;359(5):492–507. - PubMed
    1. Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Mechanisms of disease: cell death. The New England Journal of Medicine. 2009;361(16):1570–1583. - PMC - PubMed
    1. Andrews GA, Xi S, Pomerantz RG, et al. Mutation of P53 in head and neck squamous cell carcinoma correlates with BCL-2 expression and increased susceptibility to cisplatin-induced apoptosis. Head and Neck. 2004;26(10):870–877. - PubMed
    1. Ikegaki N, Katsumata M, Minna J, Tsujimoto Y. Expression of bcl-2 in small cell lung carcinoma cells. Cancer Research. 1994;54(1):6–8. - PubMed

Publication types

MeSH terms