Targeting the JAK2/STAT3 Pathway-Can We Compare It to the Two Faces of the God Janus?

Abstract

Muscle cachexia is one of the most critical unmet medical needs. Identifying the molecular background of cancer-induced muscle loss revealed a promising possibility of new therapeutic targets and new drug development. In this review, we will define the signal transducer and activator of transcription 3 (STAT3) protein's role in the tumor formation process and summarize the role of STAT3 in skeletal muscle cachexia. Finally, we will discuss a vast therapeutic potential for the STAT3-inhibiting single-agent treatment innovation that, as the desired outcome, could block tumor growth and generally prevent muscle cachexia.

Keywords: muscle cachexia; pSTAT3 inhibitors; targeted therapy.

Figure 1

Schematic representation of the signaling pathways leading to signal transducer and activator of transcription 3 (STAT3) activation. Increased levels (indicated by red arrows) of IL-6, IL-10, IL-11, VEGF, EGFR, TGF-β, JAK, Abl, or Src lead to an increase in the rate of phosphorylated form of STAT3 protein (marked with P)-P-STAT3. Moreover, increasing the intracellular JAK level activates the mTOR pathway, which can increase the level of STAT3 dimerization both in the cytoplasm and in the nucleus. Upregulated pSTAT3 levels can lead to increased expression of genes encoding anti-apoptotic proteins, cell cycle regulators, or angiogenic factors. All of this, as a consequence, can induce the formation of neoplastic cells [22,23,25,26].

Figure 2

Comparison of the consequences of excessive STAT3 activation in muscle and cancer cells. STAT3 hyperactivity in myocytes leads to an increase (marked with an up arrow) in caspase activity, leading to universal stress proteins’ (USP) involvement. In the area of muscle tissue, a decrease in myogenin and MyoD expression (marked with a down arrow), and a weakening of the AMP-activated protein kinase (AMPK)/mTOR signal pathway were observed, which induces the process of muscle cachexia. Neoplastic cells increase the level (marked with an up) of angiogenesis, metastasis, proliferation, and inhibition of apoptosis. In this case, these events lead to the progression of the neoplastic process. On the other hand, tumor cells secrete pro-inflammatory cytokines, including IL-6, which additionally stimulate the activation of STAT3 (marked with +), intensifying pathological changes in skeletal muscles and stimulating tumor progression.