Prostate cancer (PCa) is a multifactorial and biologically heterogeneous disease characterized by the aberrant activity of different regulatory pathways, including those mediated by STAT3 (Signal Transducer and Activator of Transcription 3) [1]. STAT3 is a pleiotropic protein known to be overexpressed in several tumor types, and its activation is critically implicated in the intracellular events responsible for the insurgence, development and progression of metastatic PCa [2-3].
STAT3 can exert its canonical function as transcription factor upon the phosphorylation at tyrosine residue Y705, which leads to STAT3 homodimerization and its subsequent translocation to the nuclear compartment [4]. Aside from its phosphorylation at Y705, STAT3 can also undergo a wide range of post-translational modifications (PTMs), i.e. phosphorylation at S727, acetylation at K685 and glutathionylation at C328/542, that affect STAT3 transcriptional program other than its non-genomic activities [5]. As outlined in previous studies from our laboratory, STAT3 PTMs pattern is dependent on cellular environmental conditions [6]. Under oxidative stress, typical of clinically advanced PCa, STAT3 turns out to be phosphorylated at S727, as well as S-glutathionylated at C328/542; on the other hand, acetylation of STAT3 at K685 occurs upon inflammation, predominant in tumor¿s early stage. Obtained results prove the stimulus-specificity of STAT3 PTMs, which could therefore represent suitable targets for PCa prevention, diagnosis and therapy.
On the basis of these evidence, the next step in this research is to verify whether STAT3 PTMs could be trustworthy biomarkers for PCa prognosis and monitoring. If confirmed, this scenario could provide the premise to develop a personalized therapy in PCa treatment, tailoring the pharmacological approach in order to reach individualized goals in relation to STAT3 PTMs profile.
Prostate cancer, especially as locally advanced and metastatic disease, continues to be a burden on the healthcare system. While the prognosis is good for patients diagnosed with a localized PCa, the prognosis remains poor for clinically advanced tumours. All current therapies, from androgen deprivation therapy (ADT) to chemotherapy, merely slow the progression of the disease, that remains one of the leading causes of death in men worldwide. Understanding the biological bases of the biological heterogeneity of PCa is one of the greatest challenges for the best management of PCa patients. In particular, the treatment of locally advanced and metastatic prostate cancer is currently hampered by drug resistance, and there is an urgent need to identify new therapeutic targets. A recently explored candidate target for the treatment of aggressive PCa is the transcription factor STAT3, an important oncogenic-associated protein that is constitutively activated in prostate cancer. In particular, findings of previous studies from our laboratory lead us to hypothesize that the post-translational modifications of STAT3 are closely related on PCa clinical stage and, for this reason, they could represent innovative tools to expand pharmacological, diagnostic and prevention strategies.