Signal Transducers and Activators of Transcription: Novel Targets for Anticancer Therapeutics

Abstract

The disruption of STAT signaling blocks neoplastic transformation, thus making inhibitors of STAT proteins a potential novel molecular approach to treat human cancer. Background: Through specific activation of gene expression, the family of proteins known as signal transducers and activators of transcription (STATs) converts extracellular stimuli into diverse biological responses. Beyond the normal signaling functions of STATs, recent evidence indicates that aberrant activation of STATs contributes to neoplastic transformation.Methods: Current literature pertaining to the role of STAT proteins in oncogenesis is presented. Also, the rationale for developing novel approaches to disrupt STAT signaling is discussed, and the potential of STATs as anticancer targets in treating human cancer is reviewed. Results:The discovery that certain oncoproteins constitutively activate specific STATs, coupled with observations that elevated STAT activity occurs frequently in a spectrum of human tumors, establishes a direct link between STAT activation and neoplastic transformation. Significantly, abrogation of STAT signaling blocks oncogenesis in model in vitro and in vivo systems. These results make STATs attractive targets for rational design of small molecule inhibitors and gene therapy approaches to disrupt STAT signaling. Conclusions:As a result of genetic, biochemical, and crystallographic analyses, the functional domains of STAT proteins have been well characterized. Based on these data, selective inhibitors of STAT function can be designed. Because disrupting STAT signaling has proven effective in blocking neoplastic transformation, it is proposed that STAT proteins represent promising targets for development of novel molecular therapeutics to treat human cancer. . Oil on canvas. Fig 1. -Generic structure of a STAT protein illustrating common functional domain elements shared by STAT family members. The sites of tyrosine (Y) and serine (S) phosphorylation are shown. SH2 = Src-homology 2 domain, N = amino terminus, C = carboxyl terminus.

Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers

“…It has been shown to reduce the incidence of breast cancer in high-risk diabetic patients and to improve the prognosis in patients who develop the disease. At the cellular level, metformin inhibits mTOR using both AMPK-dependent 50 and -independent mechanisms. 40 It has been shown to reduce pro-growth signaling through EGFR, MAPK and Akt pathway.…”

“…Antibodies were from the following sources: Stat3, P-Stat3(S727), P-Stat3(Y705), mTOR, P-mTOR, AMPKα, P-AMPKα (Thr172), caspase-8 (1C12), caspase-9 and caspase-3 (8G10), P-Akt (Ser473), P-Src, cleaved PARP (Cell Signaling Technology, Inc. cells were treated with increasing concentrations of each agent at a fixed ratio of 1:1,000 that was determined by their IC 50 when each compound was added to cells alone. Cell viability was determined by MTS assay.…”

Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth

“…Recent studies in animal models using a dominantnegative form of STAT3 and a constitutively active mutant of STAT3, as well as the prevalence of constitutively activated STAT3 in many human cancers, strongly suggest that STAT3 has a causal role in oncogenesis (29)(30)(31). Also, there have been reports that immunosuppressive microenvironments are elicited by the constitutive activation of STAT3 in cancer and stromal cells, including melanoma (5-7).…”

STAT3 inhibitor, cucurbitacin I, is a novel therapeutic agent for osteosarcoma

“…STAT3 is tyrosine phosphorylated and constitutively activated in many human cancer types (17–19). We first assayed STAT3 expression of the five human OS cell lines (143B, HOS, MG63, SAOS-2, and HUO9) by western blotting of the cell lysates with antibodies specific for STAT3.…”