Targeting TRIB2 expression with oral antidiabetic drugs to overcome tumour malignancy and drug-resistance

Abstract

Abstract Introduction TRIB2 is one of three members of the Tribbles family, which interacts and activates the protein kinase AKT, associated to the suppression of FOXO in melanoma, which mediate insulin action on key functions involved in cell metabolism and growth. TRIB2, recently identified as a druggable protein, has been pointed as a cause of resistance to cancer therapies, and so, modulating its expression might be a suitable strategy to overcome tumour malignancy and drug-resistance. Members from the thiazolidinediones (TZDs) family of oral antidiabetic insulin-sensitizing drugs, available in clinical settings, have been previously reported to be effective in melanoma, however there are still controversial results. Objectives Identifying new therapeutic strategies to overcome therapeutic resistance in TRIB2-positive cancers. Methodology Analyses of TRIB2’s expression levels in different samples in response to TZDs, using GEO profiles available at public data repository with the following advanced search terms: TRIB2 [gene] AND Rosiglitazone OR Pioglitazone OR Troglitazone. Results From a total of 15 independent studies, it was found that TRIB2 was up-regulated in Rosi-treated human dendritic cells, skeletal muscle from obese PCOS women treated with Pioglitazone, and liver from obese rats treated either with Pio or Troglitazone. By contrast, TRIB2 was down-regulated in white adipose tissue (WAT) from obese rats treated either with Pio or Troglitazone, in Rosi-treated mouse stromal vascular cells from inguinal WAT, and in PPARγ–overexpressed marrow mesenchymal stem cells treated with Rosiglitazone. Conclusion Although TRIB2 expression was modulated by the different TZDs in certain samples, depending on the cellular context, it was either up- or down-regulated. While further studies are needed, especially in a malignancy environment, TZDs treatment of TRIB2-positive cancer does not seem to be a valuable therapeutic strategy and might be even counter-productive.