Thesis title: STAT3 pathways: central signaling hub in carcinogenesis
The signal transducer and activator of transcription 3 (STAT3) protein is an important oncogene and a central regulator of multiple signaling pathways involved in cancer. Unlike normal cells, in which STAT3 activation is transient, tumor cells often exhibit chronic STAT3 activation, promoting proliferation, survival, angiogenesis, and metabolic reprogramming. This thesis aimed to determine whether STAT3 plays a pleiotropic role in both chemical carcinogenesis and tumor metabolism of hormone-dependent cancers, and to assess how its function may be modulated through post-translational modifications (PTMs) or interacting signaling pathways. The results show that β-HCH reduces the efficacy of chemotherapeutic drugs in different cellular models (MCF-7, H358, LNCaP, HepG2). In this context, STAT3 plays a central role: indeed, inhibiting its activity restores the effectiveness of the anticancer drugs. Subsequently, the effects of cigarette smoke condensate (CSC) were examined in HepG2 cells, showing that both STAT3 and the aryl hydrocarbon receptor (AhR) translocate to the nucleus, forming a functional regulatory circuit responsible for tumor progression. The nuclear localization of these proteins amplifies the transcription of genes such as IDO and NOX-1, promoting the generation of reactive oxygen species (ROS), activation of the non-canonical STAT3 pathway, and increased tumor aggressiveness. In more aggressive tumor models, represented in our experiments by DU-145 (prostate carcinoma) and KPL-4 (breast carcinoma) cell lines, STAT3 participates in a loop with PKM2 and HIF-1α that sustains the metabolic switch toward anaerobic glycolysis. We demonstrated that modulation of PKM2 and HIF-1α through treatment with serine and N-acetylcysteine (NAC) reduced STAT3 activity, both mitochondrial and nuclear, and reversed the Warburg effect, particularly following NAC treatment. Finally, we focused on the analysis of STAT3 PTMs in LNCaP (hormone-responsive) and DU-145 (hormone-resistant) cells, and the results revealed a differential regulation depending on tumor aggressiveness: acetylation was associated with early tumor stages, whereas poly-ADP-ribosylation correlated with highly proliferative and ROS-rich phenotypes. These findings confirm STAT3 as a central hub capable of integrating signaling, metabolism, and post-translational modifications in tumor progression.