Yasuto Akiyama1, Akira Iizuka1, Akiko Kume1, Masaru Komiyama1, Kenichi Urakami2, Tadashi Ashizawa1, Haruo Miyata1, Maho Omiya1, Masatoshi Kusuhara3, Ken Yamaguchi4. 1. Immunotherapy Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, Japan. 2. Cancer Diagnostics Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, Japan. 3. Regional Resources Division, Shizuoka Cancer Center Research Institute, Sunto-gun, Shizuoka, Japan. 4. Office of the President, Shizuoka Cancer Center Hospital, Sunto-gun, Shizuoka, Japan.
Abstract
BACKGROUND: Signal transducer and activator of transcription (STAT)3 is involved in a metabolic shift in cancer cells, the Warburg effect through its pro-oncogenic activity. To develop efficient STAT3 inhibitors against cancer cells, novel proteomic and metabolic target molecules need to be explored using multi-omics approaches in the context of STAT3 gene inhibition-mediated tumor growth suppression. MATERIALS AND METHODS: We found that short hairpin (sh)RNA-mediated STAT3 inhibition suppressed tumor growth in a highly STAT3-activated lymphoma cell line, SCC-3 cells, and we investigated the effect of STAT3 inhibition on metabolic switching using 2-dimensional differential gel electrophoresis and capillary electrophoresis-time of flight-mass spectrometry. RESULTS: We identified latexin as a proteomic marker candidate and metabolic enzymes including fructose-bisphosphate aldolase A (ALDOA) as a metabolic marker candidate for STAT3-targeting therapy using STAT3-specific shRNA gene transduction. In particular, latexin expression was up-regulated in four STAT3-activated cancer cell lines including SCC-3 transduced with STAT3-specific shRNA. The up-regulation of latexin was identified in SCC-3 tumors transplanted to nude mice after treatment with STAT3 inhibitor. CONCLUSION: Our results suggest that STAT3 inactivation reverses the glycolytic shift by down-regulating key enzymes and that it induces up-regulation of latexin as a tumor-suppressor molecule, which partially results in cancer cell apoptosis and tumor growth suppression. Copyright
BACKGROUND: Signal transducer and activator of transcription (STAT)3 is involved in a metabolic shift in cancer cells, the Warburg effect through its pro-oncogenic activity. To develop efficient STAT3 inhibitors against cancer cells, novel proteomic and metabolic target molecules need to be explored using multi-omics approaches in the context of STAT3 gene inhibition-mediated tumor growth suppression. MATERIALS AND METHODS: We found that short hairpin (sh)RNA-mediated STAT3 inhibition suppressed tumor growth in a highly STAT3-activated lymphoma cell line, SCC-3 cells, and we investigated the effect of STAT3 inhibition on metabolic switching using 2-dimensional differential gel electrophoresis and capillary electrophoresis-time of flight-mass spectrometry. RESULTS: We identified latexin as a proteomic marker candidate and metabolic enzymes including fructose-bisphosphate aldolase A (ALDOA) as a metabolic marker candidate for STAT3-targeting therapy using STAT3-specific shRNA gene transduction. In particular, latexin expression was up-regulated in four STAT3-activated cancer cell lines including SCC-3 transduced with STAT3-specific shRNA. The up-regulation of latexin was identified in SCC-3tumors transplanted to nude mice after treatment with STAT3 inhibitor. CONCLUSION: Our results suggest that STAT3 inactivation reverses the glycolytic shift by down-regulating key enzymes and that it induces up-regulation of latexin as a tumor-suppressor molecule, which partially results in cancer cell apoptosis and tumor growth suppression. Copyright
Authors: Rens Peeters; Jorge Cuenca-Escalona; Esther A Zaal; Anna T Hoekstra; Anouk C G Balvert; Marcos Vidal-Manrique; Niek Blomberg; Sjoerd J van Deventer; Rinke Stienstra; Julia Jellusova; Martin Giera; Luciana Hannibal; Ute Spiekerkoetter; Martin Ter Beest; Celia R Berkers; Annemiek B van Spriel Journal: Nat Commun Date: 2022-09-13 Impact factor: 17.694