Abstract
Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been reported to promote proliferation and survival of Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma (HL). We investigated the activity of the JAK inhibitor AZD1480 in HL-derived cell lines and determined its mechanisms of action. AZD1480 at low doses (0.1–1 μ) potently inhibited STATs phosphorylation, but did not predictably result in antiproliferative effects, as it activated a negative-feedback loop causing phosphorylation of JAK2 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), and increased IP-10, RANTES and interleukin (IL)-8 concentrations in the supernatants. Inhibition of the ERK activity by mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (UO126 and PD98059) enhanced the cytotoxic activity of AZD1480. Interestingly, submicromolar concentrations of AZD1480 demonstrated significant immunoregulatory effects by downregulating T-helper 2 cytokines and chemokines, including IL-13 and thymus- and activation-regulated chemokine, and the surface expression of the immunosuppressive programmed death ligands 1 and 2. Higher concentrations of AZD1480 (5 μ) induced G2/M arrest and cell death by inhibiting Aurora kinases. Our study demonstrates that AZD1480 regulates proliferation and immunity in HL cell lines and provides mechanistic rationale for evaluating AZD1480 alone or in combination with MEK inhibitors in HL.
Highlights
IntroductionThe Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been linked to the oncogenic process of a variety of cancers, including Hodgkin lymphoma (HL), making it an appealing target for a pathway-directed cancer therapy.[1,2,3,4] JAK/STAT activation is primarily driven by an aberrant deregulation of a network of cytokine and chemokines in the HL microenvironment (autocrine and paracrine loops involving a variety of cytokines such as, interleukin (IL)-6 and IL-13).[1,2,4] In rare cases, genomic gains of JAK2 and inactivating mutations of suppressors of cytokine signaling (SOCS) proteins have been linked to the JAK/STAT activation in HL.[5,6] After the cytokine receptor is engaged, members of the JAK family (JAK1, JAK2, JAK3 and tyrosine (Tyr) kinase 2 (TYK2)) are phosphorylated, and in turn, they phosphorylate downstream
We found p-STAT3, p-STAT5 and p-STAT6 to be expressed in the three cell lines that expressed at least one active phosphorylated member of the Janus kinase (JAK) family: HD-LM2, L-428 and L-540
We described the pleiotropic activity of AZD1480 in Hodgkin lymphoma (HL)-derived cell lines, showing a dual mechanism of action: (1) a direct dose-dependent cytotoxic effect achieved by two
Summary
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway has been linked to the oncogenic process of a variety of cancers, including Hodgkin lymphoma (HL), making it an appealing target for a pathway-directed cancer therapy.[1,2,3,4] JAK/STAT activation is primarily driven by an aberrant deregulation of a network of cytokine and chemokines in the HL microenvironment (autocrine and paracrine loops involving a variety of cytokines such as, interleukin (IL)-6 and IL-13).[1,2,4] In rare cases, genomic gains of JAK2 and inactivating mutations of suppressors of cytokine signaling (SOCS) proteins have been linked to the JAK/STAT activation in HL.[5,6] After the cytokine receptor is engaged, members of the JAK family (JAK1, JAK2, JAK3 and tyrosine (Tyr) kinase 2 (TYK2)) are phosphorylated, and in turn, they phosphorylate downstream. This leads to STAT proteins dimerization and translocation to the nucleus, where they trigger the transcription of target genes involved in cell proliferation and survival.[7]. The JAK/STAT pathway has been shown to be involved in the regulation of PD-L1 and PD-L2 expression in HL and anaplastic large cell lymphoma cells.[9,11,13]
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