Activation of the PIK3CA/AKT Pathway Suppresses Senescence Induced by an Activated RAS Oncogene to Promote Tumorigenesis

Abstract

Summary Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted application of pro-senescence cancer therapies.

Parallel pathways in RAF-induced senescence and conditions for its reversion

“…Senescent-associated b-galactosidase activity (Supplementary Figure 1) and the accumulation of IL8 and MMP1 mRNAs ( Figure 1d) were also evident after 3 days of incubation with 4-HT. IL8 and MMP1 are two secreted factors that are representative of a group of secreted proteins whose expression is increased in senescent fibroblasts (Coppe et al, 2008;Kennedy et al, 2011). Activation of GFP-RAF1-ER led to a rapid and sustained activating phosphorylation of ERK1/2 (Figure 1e) that is responsible for triggering senescence (Zhu et al, 1998).…”

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

“…In the present study, we have demonstrated that upregulation of FOXA1 blocks AKT pathway activation and is accompanied by changes in the expression of several key senescence-associated genes (p16, p27 and PTEN) in EC cells. Although our knowledge of specific mechanism of cell senescence in EC reported is limited, AKT has been shown to protect against RAS-induced senescence in other cell types (24), and several classical transcription factors related to senescence have been identified, including p16, p21 and p53 (25)(26)(27). Based on our findings, we suggest that FOXA1 promotes cell senescence in EC by interaction with p16…”

Ras, PI3K/Akt and senescence

“…5 These models have become more sophisticated in their design, allowing the introduction ExTra viEw ExTra viEw PanINs in this model. 24 Crucially, loss or deficiency of Pten (and consequent activation of Akt) led to rapid acceleration of PDAC progression. 24 Importantly, when human PDAC samples were analyzed, approximately 20% of tumors exhibited activation of PI3K/Akt/mTOR signaling, and this correlated significantly with a poorer prognosis.…”

“…24 Crucially, loss or deficiency of Pten (and consequent activation of Akt) led to rapid acceleration of PDAC progression. 24 Importantly, when human PDAC samples were analyzed, approximately 20% of tumors exhibited activation of PI3K/Akt/mTOR signaling, and this correlated significantly with a poorer prognosis. 24 These findings suggest that it may be possible for human PDACs to be divided into subsets based on the pathways misregulated, and that treatment should be selected accordingly.…”

“…24 Importantly, when human PDAC samples were analyzed, approximately 20% of tumors exhibited activation of PI3K/Akt/mTOR signaling, and this correlated significantly with a poorer prognosis. 24 These findings suggest that it may be possible for human PDACs to be divided into subsets based on the pathways misregulated, and that treatment should be selected accordingly. For example mTOR inhibitors may prove effective in tumors harboring mutations in both PI3K pathway members and in KRAS.…”