Effects of APIM-containing peptides on the regulation of the PI3K/Akt and MEK/ERK pathways
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PI3K/Akt and MEK/ERK pathways are important cellular signaling system which controls many vital cellular processes, including cell survival, proliferation, differentiation and migration. These pathways are often deregulated in many types of cancer. Interestingly, many kinases directly or indirectly involved in these pathways are found to contain the PCNA interacting motif APIM. Peptides containing the APIM sequence are able to sensitize cells to DNA damaging agents including cisplatin. This may partly be due to inhibition of the interaction between PCNA and the APIM-containing kinases by the APIM-peptides. Recently, PCNA was found in cytosol in differentiated neutrophils where it has a role in inducing apoptosis. As several kinases usually found in cytosol contain APIM, this has inspired us to explore PCNA’s unknown role in the signal transduction system. In order to investigate PCNA’s regulatory effect we exposed cells to APIM-peptides (ATX-101) as a single agent and in combination with inhibitors of the PI3K/Akt and MEK/ERK pathways and the chemotherapeutic agent cisplatin. We observed that ATX-101 increased the cytotoxicity effect of cisplatin in cancerous cell (DU145 and JJN3), but not in noncancerous cell (HEK293). Furthermore, the effects of ATX-101 and cisplatin on ERK1/2 and Akt phosphorylation are clearly different in these three cell line. Importantly, ATX-101 had clear inhibitory and stimulatory effects on the the PI3K/Akt and MEK/ERK pathways, and the effects changed over time. When comparing the effects of ATX-101 with the MEK, PI3K and Akt inhibitors we found that in some cases ATX-101 behave similarly with regard to ERK1/2 and Akt phosphorylation, but in other cases clear differences were seen. Because ATX-101 targets PCNA, these data strongly support that PCNA have a regulatory role in signal transduction.