title: Mitochondrial p32 is upregulated in Myc expressing brain cancers and mediates glutamine addiction.
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.
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fogal
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Babic
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Stanford University, Palo Alto, CA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Pingle
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.|Division of Neuro-Oncology, Department of Neurosciences, University of California, San Diego, La Jolla, CA.
authors.forename: John R
authors.initials: JR
authors.lastname: Crawford
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.|Division of Neuro-Oncology, Department of Neurosciences, University of California, San Diego, La Jolla, CA.
authors.forename: David E
authors.initials: DE
authors.lastname: Piccioni
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.Division of Neuro-Oncology, Department of Neurosciences, University of California, San Diego, La Jolla, CA.|Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, La Jolla, CA.Division of Neuro-Oncology, Department of Neurosciences, University of California, San Diego, La Jolla, CA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C087299:C1QBP protein, human; D002352:Carrier Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C489427:MYC protein, human; D024101:Mitochondrial Proteins; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine