Abstract
BackgroundThe PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. However, the implicated mechanism has been poorly characterized. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model.ResultsWe show that active STAT3 is constitutively bound to the PDK1 promoter and positively regulate PDK1 transcription through two STAT3 responsive elements. Transduction of WM9 and UACC903 melanoma cells with STAT3-small hairpin RNA decreased both PDK1 mRNA and protein levels. STAT3 knockdown also induced a decrease of the phosphorylation of AGC kinases Akt, PKC, and SGK. The inhibitory effect of STAT3 silencing on Akt phosphorylation was restored by HA-PDK1. Along this line, HA-PDK1 expression significantly blocked the cell death induced by dacarbazine plus STAT3 knockdown. This effect might be mediated by Bcl2 proteins since HA-PDK1 rescued Bcl2, Bcl-XL, and Mcl1 levels that were down-regulated upon STAT3 silencing.ConclusionsWe show that PDK1 is a transcriptional target of STAT3, linking STAT3 pathway with AGC kinases activity in melanoma. These data provide further rationale for the ongoing effort to therapeutically target STAT3 and PDK1 in melanoma and, possibly, other malignancies.
Highlights
The PI3K/RAC-alpha serine/threonine-protein kinase (Akt) and the Signal Transducer and Activator of Transcription 3 (STAT3) pathways are functionally associated in many tumor types
STAT3β negatively regulates phosphoinositide-dependent kinase 1 (PDK1) expression During experiments addressing STAT3’s role in tumorigenesis, we observed that SW1 mouse melanoma cells transduced with STAT3β presented a marked reduction in the levels of PKC phosphorylated at the hydrophobic motif (Ser660 in PKCβII) (Fig. 1a)
STAT3 regulation of PDK1 modulates phosphorylation of AGC kinases To study this mechanism in human melanoma cells using a suitable model we screened several melanoma cell lines to identify those displaying constitutive STAT3 activation
Summary
The PI3K/Akt and the STAT3 pathways are functionally associated in many tumor types. Both in vitro and in vivo studies have revealed that either biochemical or genetic manipulation of the STAT3 pathway activity induce changes in the same direction in Akt activity. Our goal was to characterize the precise mechanism linking STAT3 with the activity of Akt and other AGC kinases in cancer using melanoma cells as a model. Compelling evidence has established that aberrant STAT3 activity has a critical role in the development and progression of human tumors by promoting uncontrolled cell proliferation and Melanoma is a highly aggressive skin cancer whose incidence has been rising substantially over the last few decades worldwide [3]. Targeting of the prevalent BRAF V600E mutation (present in around 50% of patients) with vemurafenib or similar compounds produce clinical responses in most melanoma patients but all patients develop resistance and relapse, highlighting the need of new therapeutic targets [5]
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