Prolonged DEX treatment of melanoma cells resulted in constitutive increases in both STAT3 and PI-3 kinase protein levels that were correlated with increased melanoma resistance to antiproliferative hormone action.
Changes at genomic, transcriptional and post-translational levels of G-proteins and protein kinases (Ras, B-Raf) and their transcription factor effectors (c-Jun, ATF2, Stat3 and NF-kappaB) affects TNF, Fas and TRAIL receptors, which play important roles in acquiring melanoma's resistance to apoptosis.
Blocking Stat3 signaling in the melanoma cells containing high Stat3 activity results in expression of multiple chemoattractants, leading to increased migration of lymphocytes, NK cells, neutrophils, and macrophages.
Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-kappaB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas.
Our recent study found that activation of signal transducer and activator of transcription 3 (Stat3) is up-regulated in human brain metastatic cells and contributes to brain metastasis of melanoma.
Thus, the novel modified RNA oligonucleotides targeting STAT3 may serve as a useful tool to study the involvement of STAT3 in melanoma and potentially as an anti-cancer agent for melanoma.
MSCs carrying Adv-Stat3(-) caused viral amplification, depletion of Stat3 and its downstream proteins, and led to significant apoptosis in breast cancer and melanoma cell lines.
In this study, we investigated the clinical role of STAT3 and its natural inhibitor, suppressor of cytokine signaling 3 (SOCS3), in human cutaneous melanoma development and progression.
Of the genes identified, seven genes: galectin 3 (Lgals3), melanoma cell adhesion molecule (Mcam), fibronectin 1 (Fn1), signal transducer and activator of transcription 3 (Stat3), microphthalmia-associated transcription factor (Mitf), max interacting protein 1 (Max1), and non-metastatic cells 1, protein (NM23A) expressed in (Nme1) are known to be associated with melanoma, but have not yet been reported as being regulated by hypoxia in human melanoma cells.
As an alternative approach, pretreatment of melanoma cells with statin at decreased doses (5-20 μM) dramatically enhanced TRAIL-induced apoptosis, due to suppression of the NF-κB and STAT3-transcriptional targets (including COX-2) and downregulation of cFLIP-L (a caspase-8 inhibitor) protein levels.
IFNs and siRNA targeting signal transducer and activator of transcription 3 (STAT3), which is a major immune suppressive transcription factor in melanoma, were delivered simultaneously into the tumor milieu.
Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.
Furthermore, we demonstrated that melanoma B7-H3 expression was correlated to phosphorylated signal transducer and activator of transcription-3 activity level in melanoma tissues and cell lines.
These results suggest that SIPAR, functioning as a new negative regulator, inhibits STAT3 activity by enhancing its dephosphorylation and represses melanoma progression.