Research Papers:
Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer
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Abstract
Moloy T. Goswami1,2,*, Guoan Chen4,*, Balabhadrapatruni V.S.K. Chakravarthi1,2,8,*, Satya S. Pathi1,2,9, Sharath K. Anand2, Shannon L. Carskadon1,2, Thomas J. Giordano2,5, Arul M. Chinnaiyan1,2,3,5,6, Dafydd G. Thomas2,5, Nallasivam Palanisamy1,2,5,7, David G. Beer4,5, Sooryanarayana Varambally1,2,5,8
1Michigan Center for Translational Pathology, Ann Arbor, MI 48109, USA
2Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
3Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA
4Thoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
5Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA
6Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA
7Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA
8Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
9Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
*These authors have contributed equally to this work
Correspondence to:
Sooryanarayana Varambally, e-mail: [email protected]
David G. Beer, e-mail: [email protected]
Keywords: lung adenocarcinoma, amplification, purine biosynthesis, glutamine, xenograft
Received: May 04, 2015 Accepted: June 12, 2015 Published: June 23, 2015
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.
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