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PEPCK-M recoups tumor cell anabolic potential in a PKC-ζ-dependent manner

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Background: Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is expressed in all cancer types
examined and in neuroprogenitor cells. The gene is upregulated by amino acid limitation and ER-stress in an ATF4-
dependent manner, and its activity modulates the PEP/Ca2+ signaling axis, providing clear arguments for a
functional relationship with metabolic adaptations for cell survival. Despite its potential relevance to cancer
metabolism, the mechanisms responsible for its pro-survival activity have not been completely elucidated.
Methods: [U-13C]glutamine and [U-13C]glucose labeling of glycolytic and TCA cycle intermediates and their
anabolic end-products was evaluated quantitatively using LC/MS and GC/MS in conditions of abundant glucose
and glucose limitation in loss-of-function (shRNA) and gain-of-function (lentiviral constitutive overexpression) HeLa
cervix carcinoma cell models. Cell viability was assessed in conjunction with various glucose concentrations and in
xenografts in vivo.
Results: PEPCK-M levels linearly correlated with [U-13C]glutamine label abundance in most glycolytic and TCA cycle
intermediate pools under nutritional stress. In particular, serine, glycine, and proline metabolism, and the anabolic
potential of the cell, were sensitive to PEPCK-M activity. Therefore, cell viability defects could be rescued by
supplementing with an excess of those amino acids. PEPCK-M silenced or inhibited cells in the presence of
abundant glucose showed limited growth secondary to TCA cycle blockade and increased ROS.
In limiting glucose conditions, downregulation of PKC-ζ tumor suppressor has been shown to enhance survival.
Consistently, HeLa cells also sustained a survival advantage when PKC-ζ tumor suppressor was downregulated using
shRNA, but this advantage was abolished in the absence of PEPCK-M, as its inhibition restores cell growth to
control levels. The relationship between these two pathways is also highlighted by the anti-correlation observed
between PEPCK-M and PKC-ζ protein levels in all clones tested, suggesting co-regulation in the absence of glucose.
Finally, PEPCK-M loss negatively impacted on anchorage-independent colony formation and xenograft growth
in vivo.
Conclusions: All in all, our data suggest that PEPCK-M might participate in the mechanisms to regulate proteostasis
in the anabolic and stalling phases of tumor growth. We provide molecular clues into the clinical relevance of
PEPCK-M as a mechanism of evasion of cancer cells in conditions of nutrient stress.

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Articles publicats en revistes (Ciències Fisiològiques)

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PEPCK-M recoups tumor cell anabolic potential in a PKC-ζ-dependent manner