PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Abstract

Highlights d PKM1 promotes tumor growth cell intrinsically in some contexts d PKM1 activates glucose catabolism without interfering with biosynthetic pathways d PKM1-dependent autophagy/mitophagy contributes to malignancy d Expression of PKM1, but not PKM2, is sufficient to support SCLC cell proliferation

A natural variant of the sole pyruvate kinase of fission yeast lowers glycolytic flux triggering increased respiration and oxidative-stress resistance but decreased growth

“…The literature suggests that low PYK activity could help cells to retain more carbon intermediates for biosynthesis [101][102][103] . Our results, and other recent research 104 , do not support this hypothesis as cells with low Pyk1 activity grow slower and form less biomass. Our phenotypic assays also do not support the possibility that the pyk1 SNP is adaptive on specific carbon or nitrogen sources.…”

A metabolic vulnerability of small-cell lung cancer

“…Cells of origin likely influence pathway preferences in tumor cells [8]. We have now reported that bronchial neuroendocrine cells, which give rise to SCLC, were PKM1- rather than PKM-2 positive [5, 9]. Moreover, we observed that PKM1, but not PKM2, can fully support survival and/or proliferation of human SCLC cell lines, highlighting PKM1 and factors related its activity as potential targets to treat SCLC.…”

“…Our new findings also indicate that PKM1 activates autophagy in transformed MEFs [5], although how PKM1 favors SCLC tumor cell growth mechanistically remains to be addressed. SCLC cell dependency on high PK activity appears much greater than that of other cancer types, suggesting that SCLC cells have unique metabolic properties and are particularly vulnerable to down-modulation of PK activity.…”

“…To address these questions, we developed two lines of knock-in (KI) mice, each expressing either PKM1 or PKM2 [5]. Mice from both lines developed normally and were fertile, strongly suggesting that PKM1 expression itself did not significantly perturb normal cell proliferation or differentiation.…”

“…However, to date few tumors were known to express PKM1. Our new study reported the discovery that tumor cells in SCLC, the most malignant type of lung cancer, express PKM1 at high levels [5]. Cells of origin likely influence pathway preferences in tumor cells [8].…”