STAT3 in cancer: A double edged sword
Introduction
Signal Transducer and Activator of Transcription (STAT) factors become activated downstream of both extrinsic and intrinsic signals by phosphorylation on a conserved tyrosine residue mainly accomplished by receptor-associated JAK kinases [1], [2]. Tyrosine-phosphorylated (YP)-STATs form active dimers that concentrate in the nucleus to regulate the expression of target genes [3]. The family member STAT3 is canonically activated by YP downstream of numerous cytokines, growth factors and oncogenes, and is accordingly constitutively active in a high percentage of tumors and tumor-derived cell lines of both liquid and solid origin, which often become STAT3 addicted (recently reviewed by [4], [5]). Thus, STAT3 is widely considered as an oncogene and a good target for anti-cancer therapy. In keeping with the wide repertoire of distinct target genes activated in different contexts, STAT3 was reported to exert a plethora of different functions in normal as well as in transformed cells. STAT3 constitutive activity in tumours can promote cell survival and proliferation, down-modulate anti-tumour immune responses and promote tumor angiogenesis, enhance tumour invasion and metastasis by inducing epithelial to mesenchymal transition (EMT), alter the extracellular matrix through the expression of matrix metalloproteinases (MMP) and the enhancement of collagen cross-linking and tissue tension, modify cell energy metabolism and mitochondrial activity. Finally, STAT3 activity can confer tumor-initiating features to cancer cells in a number of solid tumors [4], [6], [7], [8], [9].
Not surprisingly therefore, STAT3 transcriptional functions are required for cellular transformation downstream of several oncogenes that trigger its phosphorylation on Y705 such as, for example, Src [10]. However, STAT3 is also required for Ras-mediated tumor transformation, for which YP and transcriptional activities are dispensable [11], suggesting that both transcriptional and non-transcriptional activities of STAT3 promote tumorigenesis. Despite this knowledge, and the wealth of data supporting the concept of STAT3 as an oncogene, several reports have now highlighted its ability to suppress tumor onset and/or progression.
Section snippets
STAT3 the oncogene or STAT3 the oncosuppressor?
The first indication that STAT3 tumor-promoting functions may be strongly context-dependent came from the observation that STAT3 plays a dual role in glioblastoma, and this role depends on its mutational status. While in the context of tumors driven by the type III epidermal growth factor receptor (EGFRvIII) mutation STAT3 triggered glial transformation by associating with the mutant receptor in the nucleus, in the context of PTEN loss STAT3 inhibited glial tumor transformation and growth [12].
Tyrosine phosphorylation
As mentioned in the introduction, STAT3 canonical activity as a transcription factor mainly depends on JAK kinase-mediated phosphorylation on Y705 (YP), which endows STAT3 dimers with the ability to concentrate in the nucleus, bind to DNA and activate transcription. Upstream signals that can trigger STAT3 YP range from cytokines of the IL-6 family, leptin, IL-12, IL-17, IL-10, Interferons, growth factors such as G-CSF, EGF, PDGF, and a number of oncogenes, the prototype of which are Src family
STAT3 and energy metabolism: of electron transport complexes and transcription
Energy metabolism plays a central role in tumor progression, with tumor cells often undergoing a metabolic switch known as the Warburg effect, leading to increased aerobic glycolysis and reduced mitochondrial activity [57]. STAT3 is an important player in this switch, since its constitutive transcriptional activity promotes aerobic glycolysis and down regulates mitochondrial activity by inducing HIF1α transcription while reducing the expression of electron transport complexes (ETC) [58]. In
STAT3 and redox balance: to be or not to be (oxidized)
Redox homeostasis is maintained thanks to an equilibrium between ROS production and scavenging, whose disruption may result in oxidative stress which in turn contributes to the pathogenesis of cancer, neurodegeneration and aging [77]. While controlled ROS production is involved in the signaling of growth factor and cytokine receptors, an excess of ROS can directly lead to oxidation-mediated inactivation of several protein phosphatases, indirectly activating key proliferation and survival
STAT3 as an autophagy regulator: to eat or not to eat (itself)
Autophagy, and in particular macro-autophagy, is a cellular process that delivers cytoplasmic material to lysosomes for degradation [84], and it plays ambiguous roles in tumor transformation and progression [85]. While an efficient autophagy machinery is essential to protect cells from transformation, cancer cells rely on autophagy for their survival and diffusion. Thus, fine-tuning of the autophagy process may represent an appealing strategy for both prevention and therapy of cancer. The
Both seed and soil: STAT3 and the tumor microenvironment
Tumor growth relies on the establishment of reciprocal relationships with components of the tumor microenvironment (TME), which is composed of cells of hematopoietic and mesenchymal origin. TME cell components can be either stromal resident cells or be specifically recruited to the tumor site, where they are instructed by cancer cells to acquire pro-tumorigenic features [106]. The reciprocal crosstalk among different cell types is responsible for the establishment and maintenance of the
Concluding remarks
Despite the concept of oncogenic STAT3 being widely accepted, an increasing body of data now supports the view that STAT3 functions are too variegated to be easily classified. Ultimately, the specific cellular role of STAT3 is determined by the integration of multiple signals that dictate the overall abundance of its many differentially modified forms, and consequently their sub-cellular localization and activity (see Fig. 1). Direct modulation by oxidation suggests that the effects of upstream
Acknowledgments
Work in the authors’ laboratories is supported by grants from the Italian Cancer Research Association (AIRC IG16930), the San Paolo Foundation, the Italian Ministry for the University and Research (MIUR PRIN) and the Truus and Gerrit van Riemsdijk Foundation, Liechtenstein, to V.P. L.A. and A. Camperi were the recipients of an Italian Cancer Research Foundation (FIRC) post-doctoral fellowship. A. Camporeale was the recipient of a Fondazione Veronesi post-doctoral fellowship. The authors wish to
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