AI Article Synopsis
- - Rab GTPases play a key role in protein trafficking within cells, relying on geranylgeranylation for proper function, which is facilitated by the enzyme GGDPS that produces a critical isoprenoid donor (GGPP).
- - Researchers are developing GGDPS inhibitors (GGSI) to target Rab activity, especially in aggressive childhood bone cancers like osteosarcoma and Ewing sarcoma, showing that GGSI treatment leads to cellular stress and apoptosis in cancer cell lines.
- - GGSI not only reduces tumor growth in preclinical models but also impairs cellular migration and invokes significant metabolic changes that highlight potential for GGSIs as a new therapeutic strategy for these cancers.
Article Abstract
Rab GTPases are critical regulators of protein trafficking in the cell. To ensure proper cellular localization and function, Rab proteins must undergo a posttranslational modification, termed geranylgeranylation. In the isoprenoid biosynthesis pathway, the enzyme geranylgeranyl diphosphate synthase (GGDPS) generates the 20-carbon isoprenoid donor (geranylgeranyl pyrophosphate [GGPP]), which is utilized in the prenylation of Rab proteins. We have pursued the development of GGDPS inhibitors (GGSI) as a novel means to target Rab activity in cancer cells. Osteosarcoma (OS) and Ewing sarcoma (ES) are aggressive childhood bone cancers with stagnant survival statistics and limited treatment options. Here we show that GGSI treatment induces markers of the unfolded protein response (UPR) and triggers apoptotic cell death in a variety of OS and ES cell lines. Confirmation that these effects were secondary to cellular depletion of GGPP and disruption of Rab geranylgeranylation was confirmed via experiments using exogenous GGPP or specific geranylgeranyl transferase inhibitors. Furthermore, GGSI treatment disrupts cellular migration and invasion in vitro. Metabolomic profiles of OS and ES cell lines identify distinct changes in purine metabolism in GGSI-treated cells. Lastly, we demonstrate that GGSI treatment slows tumor growth in a mouse model of ES. Collectively, these studies support further development of GGSIs as a novel treatment for OS and ES.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931648 | PMC |
| http://dx.doi.org/10.1002/ddr.22012 | DOI Listing |
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