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Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.

ABSTRACT: Increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma multiforme (GBM). This study aims to determine if serine/threonine phosphatase (protein phosphatase 6 (PP6)) is a molecular target for GBM radiosensitization treatment. The GBM orthotopic xenograft mice model was used in this study. Our data demonstrated that the protein level of PP6 catalytic subunit (PP6c) was upregulated in the GBM tissue from about 50% patients compared with the surrounding tissue or control tissue. Both the in vitro survival fraction of GBM cells and the patient survival time were highly correlated or inversely correlated with PP6c expression (R(2)=0.755 and -0.707, respectively). We also found that siRNA knockdown of PP6c reduced DNA-dependent protein kinase (DNA-PK) activity in three different GBM cell lines, increasing their sensitivity to radiation. In the orthotopic mice model, the overexpression of PP6c in GBM U87 cells attenuated the effect of radiation treatment, and reduced the survival time of mice compared with the control mice, while the PP6c knocking-down improved the effect of radiation treatment, and increased the survival time of mice. These findings demonstrate that PP6 regulates the sensitivity of GBM cells to radiation, and suggest small molecules disrupting or inhibiting PP6 association with DNA-PK is a potential radiosensitizer for GBM.

SUBMITTER: Shen Y

PROVIDER: S-EPMC3252736 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.

Shen Y Y Wang Y Y Sheng K K Fei X X Guo Q Q Larner J J Kong X X Qiu Y Y Mi J J

Cell death & disease 20111208

Increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma multiforme (GBM). This study aims to determine if serine/threonine phosphatase (protein phosphatase 6 (PP6)) is a molecular target for GBM radiosensitization treatment. The GBM orthotopic xenograft mice model was used in this study. Our data demonstrated that the protein level of PP6 catalytic subunit (PP6c) was upregulated in the GBM tissue from about 50% patie ...[more]

PMID: 22158480

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Project description:The opportunistic pathogen Candida is one of the most common causes of nosocomial bloodstream infections. Because candidemia is associated with high mortality rates and because the incidences of multidrug-resistant Candida are increasing, efforts to identify novel targets for the development of potent antifungals are warranted. Here, we describe the structure and function of the first member of a family of protein phosphatases that is specific to fungi, protein phosphatase Z1 (PPZ1) from Candida albicans We show that PPZ1 not only is active but also is as susceptible to inhibition by the cyclic peptide inhibitor microcystin-LR as its most similar human homolog, protein phosphatase 1α (PP1α [GLC7 in the yeast Saccharomyces cerevisiae]). Unexpectedly, we also discovered that, despite its 66% sequence identity to PP1α, the catalytic domain of PPZ1 contains novel structural elements that are not present in PP1α. We then used activity and pulldown assays to show that these structural differences block a large subset of PP1/GLC7 regulatory proteins from effectively binding PPZ1, demonstrating that PPZ1 does not compete with GLC7 for its regulatory proteins. Equally important, these unique structural elements provide new pockets suitable for the development of PPZ1-specific inhibitors. Together, these studies not only reveal why PPZ1 does not negatively impact GLC7 activity in vivo but also demonstrate that the family of fungus-specific phosphatases-especially PPZ1 from C. albicans-are highly suitable targets for the development of novel drugs that specifically target C. albicans without cross-reacting with human phosphatases. Candida albicans is a medically important human pathogen that is the most common cause of fungal infections in humans. In particular, approximately 46,000 cases of health care-associated candidiasis occur each year in the United States. Because these infections are associated with high mortality rates and because multiple species of Candida are becoming increasingly resistant to antifungals, there are increasing efforts to identify novel targets that are essential for C. albicans virulence. Here we use structural and biochemical approaches to elucidate how a member of a fungus-specific family of enzymes, serine/threonine phosphatase PPZ1, functions in C. albicans We discovered multiple unique features of PPZ1 that explain why it does not cross-react with, and in turn compete for, PP1-specific regulators, a long-standing question in the field. Most importantly, however, these unique features identified PPZ1 as a potential target for the development of novel antifungal therapeutics that will provide new, safe, and potent treatments for candidiasis in humans.

Dataset Information

Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.

Publications

Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.

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