Fig. 1

Molecular links between the two major survival pathways MAPK/ERK and PI3K/AKT/mTOR. The vast majority of tumors develop because of oncogenic mutations in the PI3K, Akt, PTEN, ras and related key genes, which are directly involved in initiating of PI3K/Akt/mTOR and/or MAPK/ERK signaling pathways. These pathways are vital for fast growing cells and cell proliferation. In tumor cells, MAPK/ERK and PI3K/AKT/mTOR pathways cooperate in downregulating of the pro-apoptotic tumor suppressor Par-4. Activation of MEK via ras (MAPK/ERK-pathway) induces upregulation of DNA-methylases (Dnmt-1 and Dnmt-3) which methylate specific sites in the promoter of the Par-4 gene hereby silencing the Par-4-gene. On the other hand, activated Akt, a key member of PI3K/Akt/mTOR-signaling, phosphorylates the Par-4 molecule at serine residue 249 hereby triggering downregulation of the Par-4 activity. Deactivation of the Par-4-function enables tumor cells to escape apoptosis and thus ensures their longevity. At the same time, activated PI3K/Akt/mTOR-signaling regulates the activity of G6PD via SREBP1-c. Activated G6PD supplies tumor cells with pentoses for the synthesis of nucleic acids and, even more important, ensures NADP/NADPH-equilibrium, which is vital for antioxidative defense. Withaferin A and 3,3′-diindolylmethane are known Par-4-activators. Aspirin, nicotinamide, steroids are inhibitors of G6PD