Effect of STAT3 Inhibition on the Metabolic Switch in a Highly STAT3-activated Lymphoma Cell Line

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.