JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells

Abstract

Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2-regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1-3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2-dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2-stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2-induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2-stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2-dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2-induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/ mTORC1 pathway in IL-2-responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2-dependent ATL.

Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

“…6B). JAK has been reported to activate the PI3K/AKT pathway in cancer cells (21). To determine whether FAK was upstream or downstream of PI3K and AKT signaling, the ability of constitutively active PI3K to overcome targeted pathway deletion was analyzed (Fig.…”

Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer

“…However, no effect was found on hTERT mRNA expression (26). Evidence for a regulatory role for mTOR on telomerase activity has been found in the case of adult T cell leukaemia (27). hTERT activity has been suggested as a surrogate for rapamycin antineoplastic activity in endometrial carcinoma (25).…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…The signaling pathways involved were found to be the JAK/ STAT pathway and the JAK/PI3K/AKT/HSP90/mTORC1 pathway in these ATL cells. 126 Due to the similarity between morphology of these cytokines and their effects on telomerase activity, one can postulate that they are acting via similar mechanisms. As mentioned, the JAK/ STAT pathway has been identified as playing an important role.…”

“…Both STAT3 and STAT5 are directly involved in telomerase transcription. 126,127 Despite these predictions from the involvement of shared signaling pathways, further research is required to clarify the effects of these cytokines on telomerase in both CD8 C and NK cells. Currently, only IL-15 and IL-7 have been shown to enhance telomerase activity in CD8 C cells with no published research describing their effects on telomerase activity in NK cells.…”

“…As discussed, IL-2 increases telomerase in leukemia cells, promoting tumor growth. 126 However, IL-15 only stimulates telomerase in immune effector cells in the presence of prostate cancer cells without any effect on prostate cancer cell proliferation. 120 Further research is required to determine effects of the different cytokines on different cancers.…”