[HTML][HTML] Stat proteins and oncogenesis

J Bromberg - The Journal of clinical investigation, 2002 - Am Soc Clin Investig
The Journal of clinical investigation, 2002Am Soc Clin Investig
The first reports of persistently tyrosine-phosphorylated (that is, persistently activated) STAT
proteins in primary cancers and tumor-derived cell lines came shortly after the discovery of
the STATs (Table 1). Subsequent work showed that, in a number of tumorderived cell lines,
the STATs, particularly STAT3, are required to maintain a transformed phenotype. STAT5 is
also commonly found to be constitutively activated in certain malignancies, especially
leukemias and lymphomas (Table 1). The expression of fusion proteins that cause …
The first reports of persistently tyrosine-phosphorylated (that is, persistently activated) STAT proteins in primary cancers and tumor-derived cell lines came shortly after the discovery of the STATs (Table 1). Subsequent work showed that, in a number of tumorderived cell lines, the STATs, particularly STAT3, are required to maintain a transformed phenotype. STAT5 is also commonly found to be constitutively activated in certain malignancies, especially leukemias and lymphomas (Table 1). The expression of fusion proteins that cause heightened or unrestrained JAK2, PDGF-R, or ABL signaling can lead to the constitutive activation of STAT5. Work in murine models shows that bcr-abl–and v-abl–induced leukemias do not require Stat5 (17) but that this protein is required for a myeloproliferative disorder that results from a TEL-JAK fusion (18). Stat3-deficient murine T cells, mammary epithelial cells, macrophages, fibroblasts, and keratinocytes are viable, relatively normal cells with subtle defects typically involving the regulation of apoptosis (19). Thus, in these few examples, Stat3 is not essential for viability of normal cells. In contrast, many cancer-derived cell lines that contain consitutively activated STAT3 are dependent on this protein and undergo growth arrest or apoptosis when treated with antisense or dominant negative constructs directed at STAT3. Direct evidence that STAT3 signaling is oncogenic comes from work with a spontaneously dimerizingmutant form of STAT3, STAT3-C, which does not require tyrosine phosphorylation to be activated yet is capable of transforming fibroblasts (20). There are no known naturally occurring mutations of STAT3 that lead to its constitutive activation and subsequent transformation of cells. In all naturally occurring tumors and in oncogene-transformed cells, STAT3 activation is typically dependent upon dysregulated growth factor receptor tyrosine kinases or their associated Jak kinases. Thus, in the case of thyroid cancers associated with an aberrantly regulated Ret receptor tyrosine kinase, Schuringa et al.(21) have found that transformation by Ret requires phosphorylation and activation of STAT3. Similarly, expression of a dominant negative STAT3 abrogates cellular transformation in the acute myelogenous leukemia (AML) and gastrointestinal stromal cell tumors (GISTs) associated with activating mutations in the receptor c-kit (22). STAT3 is also persistently activated in Hodgkin disease, where AG490, an inhibitor of JAK2 and STAT3 phosphorylation, can be used to inhibit tumor growth (23). In primary prostate cancer specimens and prostate cancer–derived cell lines, likewise, STAT3 is activated, and the introduction of antisense to STAT3 provokes tumor cell apoptosis (24, 25). Finally, persistently activated STAT3 and JAK2 are found in the rare malignancy large granular lymphocyte leukemia; treatments that block STAT3 expression or function cause cancer cell death by upregulating the proapoptotic protein Fas and downregulating the antiapoptotic Mcl-1 (26, 27).
Antisense reagents and dominant negative constructs directed at STAT3, as well as Jak inhibitors such as AG490, thus hold the promise of tumor-specific growth inhibition and appear to be useful against a range of cancer cells (Table 1). In addition, Jove and colleagues recently developed a novel approach to blocking STAT3 function, using a phosphopeptide tethered to a protein transduction domain (28). This peptide
The Journal of Clinical Investigation