Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation

Abstract

SUMMARY Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.

Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

“…Several mouse models have been reported to investigate GOF properties of p53 mutants (6)(7)(8)(9)(10). In addition to loss of WT p53 function, the ability of GOF p53 to activate transcription of proliferative genes (11)(12)(13) or to deregulate signaling pathways (14) has been connected to its oncogenic properties. Inhibition of tumor formation by knockdown of endogenous mutant p53 has been demonstrated in human lung cancer cells using RNAi and knockin (KI) mouse models (15,16).…”

Protéger et sévir : p53, métabolisme et suppression tumorale

“…B. Les mutants oncogéniques (ponctuels) de p53 fréquemment associés aux cancers humains présentent des fonctions métaboliques profondément altérées, et souvent inversées. Plusieurs d'entre eux promeuvent en effet la glycolyse (et l'effet Warburg) en stimulant la relocalisation membranaire du transporteur du glucose, Glut1, et/ou en inhibant l'activation de la kinase dépendante de l'AMP (AMPK) induite par un stress métabolique [48,49]. D'autres mutants peuvent agir comme co-activateurs des facteurs de transcription SREBP (sterol-regulatory element-binding protein), alors que p53 normale réprime l'expression du gène codant SREBP-1.…”

“…De plus, des allèles de p53 fréquemment associés aux cancers humains présentent de nouvelles propriétés (mutants néomorphes) participant activement à la transformation (Figure 4) [1,4,5]. Ainsi, plusieurs mutations ponctuelles altèrent ou inversent les fonctions métaboliques de p53 : les mutants correspondants promeuvent l'effet Warburg et/ou la voie du méva-lonate et la synthèse des acides gras, ce qui contribue à leur effet tumorigène [48][49][50] (Tableau II) (Figure 5). Il apparaît donc que les multiples influences de p53 sur le métabolisme et la survie cellulaire, sa capacité à moduler la stabilité génétique, et sa propension à acquérir une nouvelle fonction par un seul changement d'acide aminé, en font aussi un outil de choix pour la « gymnastique oncogénétique » [15] permettant aux cellules tumorales de s'adapter et croître dans des environnements variables et souvent défavorables.…”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…In addition to direct regulation of key metabolic checkpoints, AMPK may also inhibit tumorigenesis through upregulation of transcription factors such as the tumor suppressor p53, which is mutated in approximately 80% of all cancers (He et al ., 2014; Jones et al ., 2005; Lee et al ., 2012). Mutation or genetic deficiency of p53 may also act to suppress AMPK activity (Zhou et al ., 2014), suggesting that the activities of p53 and AMPK may be intimately linked to match energy availability with cell proliferation (Adamovich et al ., 2014). While many studies have examined the interaction between AMPK and the tumor suppressor p53 in cultured cells, the importance of this pathway to tumorigenesis has not been studied in vivo .…”