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Mitochondrial p32 is upregulated in Myc expressing brain cancers and mediates glutamine addiction.

Fogal V, Babic I, Chao Y, Pastorino S, Mukthavaram R, Jiang P, Cho YJ, Pingle SC, Crawford JR, Piccioni DE, Kesari S - Oncotarget (2015)

Bottom Line: Loss of p32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal.Finally, we provide evidence that p32 expression contributes to Myc-induced glutamine addiction of cancer cells.Our findings suggest that Myc promotes the expression of p32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.

ABSTRACT
Metabolic reprogramming is a key feature of tumorigenesis that is controlled by oncogenes. Enhanced utilization of glucose and glutamine are the best-established hallmarks of tumor metabolism. The oncogene c-Myc is one of the major players responsible for this metabolic alteration. However, the molecular mechanisms involved in Myc-induced metabolic reprogramming are not well defined. Here we identify p32, a mitochondrial protein known to play a role in the expression of mitochondrial respiratory chain complexes, as a critical player in Myc-induced glutamine addiction. We show that p32 is a direct transcriptional target of Myc and that high level of Myc in malignant brain cancers correlates with high expression of p32. Attenuation of p32 expression reduced growth rate of glioma cells expressing Myc and impaired tumor formation in vivo. Loss of p32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal. Finally, we provide evidence that p32 expression contributes to Myc-induced glutamine addiction of cancer cells. Our findings suggest that Myc promotes the expression of p32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells.

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Upregulation of p32 in malignant brain tumorsMatched normal and malignant brain tissue (A), and a human brain tumor array (B) were stained with a polyclonal anti-p32 antibody. P32 positive staining for each core was quantified using Aperio software (B left panel). The array contains over 100 cases of gliomas, including both astrocytoma and medulloblastoma subtypes, and normal tissue. The two-tailed Student t test was used for statistical analysis. Significant differences are indicated using the standard Michelin Guide scale (p < 0.05 (*), significant; p < 0.01 (**), highly significant; p < 0.001 (***) extremely significant. Representative cores, at low (10x) and high (400x) magnification, of normal cerebellum and astrocytomas of different malignancy grade (GR) are indicated on the right panel of Figure 1B. (C) Increasing expression of p32/C1QBP correlates with poor survival. Shown is a survival plot for mesenchymal subtype of GBM based on increasing expression of p32/C1QBP using Affymetrix HT_HG-U133A. Plot generated using the Glioblastoma Bio Discovery Portal (http://robtcga.nci.nih.gov/#genes).
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Figure 1: Upregulation of p32 in malignant brain tumorsMatched normal and malignant brain tissue (A), and a human brain tumor array (B) were stained with a polyclonal anti-p32 antibody. P32 positive staining for each core was quantified using Aperio software (B left panel). The array contains over 100 cases of gliomas, including both astrocytoma and medulloblastoma subtypes, and normal tissue. The two-tailed Student t test was used for statistical analysis. Significant differences are indicated using the standard Michelin Guide scale (p < 0.05 (*), significant; p < 0.01 (**), highly significant; p < 0.001 (***) extremely significant. Representative cores, at low (10x) and high (400x) magnification, of normal cerebellum and astrocytomas of different malignancy grade (GR) are indicated on the right panel of Figure 1B. (C) Increasing expression of p32/C1QBP correlates with poor survival. Shown is a survival plot for mesenchymal subtype of GBM based on increasing expression of p32/C1QBP using Affymetrix HT_HG-U133A. Plot generated using the Glioblastoma Bio Discovery Portal (http://robtcga.nci.nih.gov/#genes).

Mentions: Immunohistochemical analysis of matched normal and malignant brain tumor tissues from patients revealed higher p32 reactivity in tumor tissue compared to normal brain (Fig. 1A upper panels). Staining was predominantly cytoplasmic, but membrane staining was also evident. In normal brain tissues, p32 expression was confined to pyramidal neurons. In agreement with these observations, a survey of a human brain tumor tissue array revealed that p32 is upregulated in most glioma cases, with significant enhanced expression in malignant (grade 2, 3 and 4) compared to both normal and hyperplastic (G1) tissues (Fig. 1B). To assess clinical relevance of increased expression of p32 in malignant brain tumors, we examined correlation between patient survival and p32 expression level. Analysis of TCGA data using the GBM Bio Discovery Portal (http://robtcga.nci.nih.gov/#genes) revealed a significant correlation between high p32 expression and decreased survival (p = 0.0548) (Fig. 1C).


Mitochondrial p32 is upregulated in Myc expressing brain cancers and mediates glutamine addiction.

Fogal V, Babic I, Chao Y, Pastorino S, Mukthavaram R, Jiang P, Cho YJ, Pingle SC, Crawford JR, Piccioni DE, Kesari S - Oncotarget (2015)

Upregulation of p32 in malignant brain tumorsMatched normal and malignant brain tissue (A), and a human brain tumor array (B) were stained with a polyclonal anti-p32 antibody. P32 positive staining for each core was quantified using Aperio software (B left panel). The array contains over 100 cases of gliomas, including both astrocytoma and medulloblastoma subtypes, and normal tissue. The two-tailed Student t test was used for statistical analysis. Significant differences are indicated using the standard Michelin Guide scale (p < 0.05 (*), significant; p < 0.01 (**), highly significant; p < 0.001 (***) extremely significant. Representative cores, at low (10x) and high (400x) magnification, of normal cerebellum and astrocytomas of different malignancy grade (GR) are indicated on the right panel of Figure 1B. (C) Increasing expression of p32/C1QBP correlates with poor survival. Shown is a survival plot for mesenchymal subtype of GBM based on increasing expression of p32/C1QBP using Affymetrix HT_HG-U133A. Plot generated using the Glioblastoma Bio Discovery Portal (http://robtcga.nci.nih.gov/#genes).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359224&req=5

Figure 1: Upregulation of p32 in malignant brain tumorsMatched normal and malignant brain tissue (A), and a human brain tumor array (B) were stained with a polyclonal anti-p32 antibody. P32 positive staining for each core was quantified using Aperio software (B left panel). The array contains over 100 cases of gliomas, including both astrocytoma and medulloblastoma subtypes, and normal tissue. The two-tailed Student t test was used for statistical analysis. Significant differences are indicated using the standard Michelin Guide scale (p < 0.05 (*), significant; p < 0.01 (**), highly significant; p < 0.001 (***) extremely significant. Representative cores, at low (10x) and high (400x) magnification, of normal cerebellum and astrocytomas of different malignancy grade (GR) are indicated on the right panel of Figure 1B. (C) Increasing expression of p32/C1QBP correlates with poor survival. Shown is a survival plot for mesenchymal subtype of GBM based on increasing expression of p32/C1QBP using Affymetrix HT_HG-U133A. Plot generated using the Glioblastoma Bio Discovery Portal (http://robtcga.nci.nih.gov/#genes).
Mentions: Immunohistochemical analysis of matched normal and malignant brain tumor tissues from patients revealed higher p32 reactivity in tumor tissue compared to normal brain (Fig. 1A upper panels). Staining was predominantly cytoplasmic, but membrane staining was also evident. In normal brain tissues, p32 expression was confined to pyramidal neurons. In agreement with these observations, a survey of a human brain tumor tissue array revealed that p32 is upregulated in most glioma cases, with significant enhanced expression in malignant (grade 2, 3 and 4) compared to both normal and hyperplastic (G1) tissues (Fig. 1B). To assess clinical relevance of increased expression of p32 in malignant brain tumors, we examined correlation between patient survival and p32 expression level. Analysis of TCGA data using the GBM Bio Discovery Portal (http://robtcga.nci.nih.gov/#genes) revealed a significant correlation between high p32 expression and decreased survival (p = 0.0548) (Fig. 1C).

Bottom Line: Loss of p32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal.Finally, we provide evidence that p32 expression contributes to Myc-induced glutamine addiction of cancer cells.Our findings suggest that Myc promotes the expression of p32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells.

View Article: PubMed Central - PubMed

Affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.

ABSTRACT
Metabolic reprogramming is a key feature of tumorigenesis that is controlled by oncogenes. Enhanced utilization of glucose and glutamine are the best-established hallmarks of tumor metabolism. The oncogene c-Myc is one of the major players responsible for this metabolic alteration. However, the molecular mechanisms involved in Myc-induced metabolic reprogramming are not well defined. Here we identify p32, a mitochondrial protein known to play a role in the expression of mitochondrial respiratory chain complexes, as a critical player in Myc-induced glutamine addiction. We show that p32 is a direct transcriptional target of Myc and that high level of Myc in malignant brain cancers correlates with high expression of p32. Attenuation of p32 expression reduced growth rate of glioma cells expressing Myc and impaired tumor formation in vivo. Loss of p32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal. Finally, we provide evidence that p32 expression contributes to Myc-induced glutamine addiction of cancer cells. Our findings suggest that Myc promotes the expression of p32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells.

Show MeSH
Related in: MedlinePlus