Oncotarget. 2015 Jun 23. [Epub ahead of print]
Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer.
Goswami MT, Chen G, Chakravarthi BV, Pathi SS, Anand SK, Carskadon SL, Giordano TJ, Chinnaiyan AM, Thomas DG, Palanisamy N, Beer DG, Varambally S
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.
- PMID:26140362
