The IGF-1R/AKT pathway determines cell fate in response to p53

Abstract

p53 that is activated in response to DNA-damaging stress can induce apoptosis or either transient or permanent cell cycle arrests. Apoptosis and permanent cell cycle arrest (senescence) are bona-fide tumor suppressor mechanisms through which p53 inhibits cancer cell survival. In contrast, transient cell cycle arrests induced by p53 can increase survival by allowing cells time to repair their DNA before proceeding with cell division. Mechanisms that control the choice of response to p53 (apoptosis vs arrest) are not fully understood. There is abundant crosstalk between p53 and the IGF-1R/AKT/mTORC1 signaling pathway. Recent studies indicate this crosstalk can determine the choice of response to p53. These findings have clear implications for the potential use of IGF-1R pathway inhibitors against p53 wild-type or p53-null or mutant cancers.

Fig 1. P53 induced by stress can promote survival, senescence, or apoptosis

Wild-type p53 is expressed at low levels and inactive in most cells. However, p53 is stabilized and activated in response to DNA damage, aberrant oncogene signaling, and other stresses that could potentially drive a normal cell towards tumorigenesis. P53 that is stabilized and activated in response to these stresses can promote survival, senescence, or apoptosis. Factors that can determine the choice of response to p53 are listed.

Fig 2. Negative crosstalk between p53 and the IGF-1R/AKT/mTORC1 pathway

p53 activated by DNA damage can inhibit the IGF-1R/AKT/mTORC1 pathway at multiple points to block proliferation, growth, and survival. AKT-mediated phosphorylation of MDM2 can increase the ability of MDM2 to degrade p53. mTORC1-dependent cell growth is inhibited in response to low energy or nutrient levels. Low glucose levels activate AMPK which then phosphorylates and activates TSC2, leading to inhibition of mTORC1. AMPK also promotes p53 phosphorylation at S15, resulting in p53-mediated cell cycle arrest. Amino acid depletion can inhibit mTORC1 by promoting dissociation of mTORC1 from the lysosome. Amino acid depletion can also activate p53 resulting in p53-dependent cell cycle arrest.

Fig 3. Positive crosstalk between p53 and the IGF-1R/AKT/mTORC1 pathway

The IGF-1R/AKT/mTORC1 pathway can be activated in response to DNA damaging stress. The IGF-1R/AKT/mTORC1 pathway was less activated in cells where p53 was depleted by shRNA, indicating p53 can contribute to IGF-1R/AKT/mTORC1 activation. One way in which this might occur is through p53-dependent induction of IGFBP-3, which can both inhibit and potentiate IGF1 signaling. AKT activated in response to DNA damage can stabilize p53 by phosphorylating GSK3b and inhibiting p53 degradation mediated by the MDM2 and GSK3b. mTORC1 can promote p53 protein synthesis.

Fig. 4. IGF-1R/AKT/mTORC1 signaling inhibits p53-dependent apoptosis and promotes p53-dependent senescence

(Left) DNA damaging stress stabilizes p53 and activates the IGF-1R pathway. AKT inhibits p53-dependent apoptosis by inhibiting GSK3b and reducing TIP60-dependent acetylation of p53 at K120. At the same time, mTORC1 activated downstream of AKT promotes p53 protein synthesis. mTORC1 activity contributes to p53-mediated senescence. (Right) IGF-1R and AKT inhibitors increase p53-dependent apoptosis by increasing GSK3b activity, which increases TIP60-dependent acetylation of p53 at K120. At the same time, IGF-1R and AKT inhibitors block mTORC1 activity and mTORC1-dependent p53 synthesis, thus reducing p53-mediated senescence.

Fig. 5. In p53-null cells, IGF-1R/AKT inhibition stabilizes p27 which then mediates a protective G1-arrest that promotes repair and survival

(Left) DNA damaging stress activates the IGF-1R pathway in p53-null cells. Activated AKT promotes survival but also inhibits p27, which could otherwise promote a protective G1-arrest and survival. (Right) IGF-1R and AKT inhibition reduces AKT-mediated survival, but also restores p27, which then mediates a G1-arrest that allows DNA repair to promote survival.