The Cooperative Relationship between STAT5 and Reactive Oxygen Species in Leukemia: Mechanism and Therapeutic Potential

Abstract

Reactive oxygen species (ROS) are now recognized as important second messengers with roles in many aspects of signaling during leukemogenesis. They serve as critical cell signaling molecules that regulate the activity of various enzymes including tyrosine phosphatases. ROS can induce inactivation of tyrosine phosphatases, which counteract the effects of tyrosine kinases. ROS increase phosphorylation of many proteins including signal transducer and activator of transcription-5 (STAT5) via Janus kinases (JAKs). STAT5 is aberrantly activated through phosphorylation in many types of cancer and this constitutive activation is associated with cell survival, proliferation, and self-renewal. Such leukemic activation of STAT5 is rarely caused by mutation of the STAT5 gene itself but instead by overactive mutant receptors with tyrosine kinase activity as well as JAK, SRC family protein tyrosine kinases (SFKs), and Abelson murine leukemia viral oncogene homolog (ABL) kinases. Interestingly, STAT5 suppresses transcription of several genes encoding antioxidant enzymes while simultaneously enhancing transcription of NADPH oxidase. By doing so, STAT5 activation promotes an overall elevation of ROS level, which acts as a feed-forward loop, especially in high risk Fms-related tyrosine kinase 3 (FLT3) mutant leukemia. Therefore, efforts have been made recently to target ROS in cancer cells. Drugs that are able to either quench ROS production or inversely augment ROS-related signaling pathways both have potential as cancer therapies and may afford some selectivity by activating feedback inhibition of the ROS-STAT5 kinome. This review summarizes the cooperative relationship between ROS and STAT5 and explores the pros and cons of emerging ROS-targeting therapies that are selective for leukemia characterized by persistent STAT5 phosphorylation.

Oxymatrine Attenuates Tumor Growth and Deactivates STAT5 Signaling in a Lung Cancer Xenograft Model

“…For example, a small molecular weight compound containing a phosphotyrosyl-mimicking salicylic acid group has been shown to efficiently bind to the SH2 domain of STAT5 and inhibit STAT5-SH2 domain protein interactions in leukemic cells [93]. There are also several molecules that have been shown to inhibit STAT5 phosphorylation and inhibit leukemia cell proliferation [94,95,96,97]. Some recent studies have also reported that natural pharmacological agents such as formononetin can modulate the STAT5 signaling pathway in multiple myeloma cells, and these compounds may have tremendous potential in the prevention and therapy of cancer [39,40,41,42,43,44].…”

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

“…[166][167][168]. Another proposed mechanism of FLT3-ITD-driven ROS production involves interaction of STAT5 with RAC1, a small GTPase protein, which is an essential component of NADPH oxidase [130,169]. Interestingly, ROS can increase phosphorylation of STAT5 via JAK, which acts as a feed-forward loop [169].…”

“…Another proposed mechanism of FLT3-ITD-driven ROS production involves interaction of STAT5 with RAC1, a small GTPase protein, which is an essential component of NADPH oxidase [130,169]. Interestingly, ROS can increase phosphorylation of STAT5 via JAK, which acts as a feed-forward loop [169]. It was demonstrated that inhibition of FLT3-ITD not only decreased tyrosine phosphorylation of STAT5 but also reduced RAC1 activity and its binding to NOX [170].…”

Discovery of Oxazol-2-amine Derivatives as Potent Novel FLT3 Inhibitors

“…The phosphorylation of STAT5 increases ROS generation through direct association with the GTP-binding protein RAC1 in FLT3-ITD + AML cells [9]. Increased ROS levels trigger DNA oxidation, genomic instability, DNA DSB, and error-prone DNA damage repair, whereas the enhanced DNA repair activities allow mutagenesis and malignancy, leading to the acquisition of genomic changes and aggressive AML [17,18]. Genomic instability is a pathologic feature of FLT3-ITD + AML [19]; therefore, inhibition of DNA damage repair can induce the death of FLT3-ITD + AML cells.…”