title: Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer.
abstract: Cancer cells exhibit altered metabolism including aerobic glycolysis that channels several glycolytic intermediates into de novo purine biosynthetic pathway. We discovered increased expression of phosphoribosyl amidotransferase (PPAT) and phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) enzymes of de novo purine biosynthetic pathway in lung adenocarcinomas. Transcript analyses from next-generation RNA sequencing and gene expression profiling studies suggested that PPAT and PAICS can serve as prognostic biomarkers for aggressive lung adenocarcinoma. Immunohistochemical analysis of PAICS performed on tissue microarrays showed increased expression with disease progression and was significantly associated with poor prognosis. Through gene knockdown and over-expression studies we demonstrate that altering PPAT and PAICS expression modulates pyruvate kinase activity, cell proliferation and invasion. Furthermore we identified genomic amplification and aneuploidy of the divergently transcribed PPAT-PAICS genomic region in a subset of lung cancers. We also present evidence for regulation of both PPAT and PAICS and pyruvate kinase activity by L-glutamine, a co-substrate for PPAT. A glutamine antagonist, 6-Diazo-5-oxo-L-norleucine (DON) blocked glutamine mediated induction of PPAT and PAICS as well as reduced pyruvate kinase activity. In summary, this study reveals the regulatory mechanisms by which purine biosynthetic pathway enzymes PPAT and PAICS, and pyruvate kinase activity is increased and exposes an existing metabolic vulnerability in lung cancer cells that can be explored for pharmacological intervention.
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Moloy T
authors.initials: MT
authors.lastname: Goswami
authors.affiliation: Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Balabhadrapatruni V S K
authors.initials: BV
authors.lastname: Chakravarthi
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Satya S
authors.initials: SS
authors.lastname: Pathi
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sharath K
authors.initials: SK
authors.lastname: Anand
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Carskadon
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.affiliation: Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000368:Aged; D000582:Amidophosphoribosyltransferase / Q000378:metabolism*; D000782:Aneuploidy; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002262:Carboxy-Lyases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002645:Chickens; D003980:Diazooxonorleucine / Q000737:chemistry; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010453:Peptide Synthases / Q000378:metabolism*; D011379:Prognosis; D011687:Purines / Q000737:chemistry
chemical_list: D014408:Biomarkers, Tumor; D011687:Purines; D003980:Diazooxonorleucine; D005973:Glutamine; D000582:Amidophosphoribosyltransferase; D002262:Carboxy-Lyases; C022378:phosphoribosylaminoimidazole carboxylase; D010453:Peptide Synthases; C022379:phosphoribosylaminoimidazole-succinocarboxamide synthetase; C030985:purine
keywords: amplification; glutamine; lung adenocarcinoma; purine biosynthesis; xenograft