title: Acquired STAT4 deficiency as a consequence of cancer chemotherapy.
abstract: Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is activated by IL-12 signaling and promotes Th1-cell differentiation and IFN-γ production. Defective IFN-γ production because of STAT4 mRNA and protein deficiency occurs after autologous stem cell transplantation for lymphoma. In the present study, we investigated the mechanisms of STAT4 deficiency in lymphoma patients. The tumor-bearing state is not responsible, because STAT4 levels were not significantly different in PBMCs obtained from healthy control subjects compared with those from lymphoma patients before treatment. STAT4 protein levels were significantly decreased in PBMCs and T cells obtained from lymphoma patients after standard-dose chemotherapy. Furthermore, treatment of control PBMC cultures or a natural killer cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished, IL-12-induced IFN-γ production. Translation of STAT4 protein was not impaired in chemotherapy-treated cells, whereas the STAT4 protein half-life was significantly reduced. Chemotherapy drugs promoted the ubiquitination and proteasomal degradation of STAT4. Treatment with the proteasome inhibitor bortezomib reversed chemotherapy-induced STAT4 deficiency and defective IFN-γ production. We conclude that acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy, results that have important implications for the design of optimal immunotherapy for lymphoma.
authors: Department of Biology, Indiana University-Purdue University Indianapolis School of Science, Indianapolis, IN 46202, USA.
authors: Ivan P
authors: IP
authors: Lupov
authors: Larry
authors: L
authors: Voiles
authors: Ling
authors: L
authors: Han
authors: Allysia
authors: A
authors: Schwartz
authors: Manuel
authors: M
authors: De La Rosa
authors: Kinnari
authors: K
authors: Oza
authors: David
authors: D
authors: Pelloso
authors: Ravi P
authors: RP
authors: Sahu
authors: Jeffrey B
authors: JB
authors: Travers
authors: Michael J
authors: MJ
authors: Robertson
authors: Hua-Chen
authors: HC
authors: Chang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002330:Carmustine / Q000009:adverse effects / Q000494:pharmacology; D002478:Cells, Cultured; D004347:Drug Interactions; D005047:Etoposide / Q000009:adverse effects* / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; C508594:IL2 protein, human; D007376:Interleukin-2; D011719:Pyrazines; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D025801:Ubiquitin; D018664:Interleukin-12; D000069286:Bortezomib; D005047:Etoposide; D002330:Carmustine