Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma
ABSTRACT
Although new analogues of immunomodulatory drugs (IMiDs) are being developed for MM, the molecular mechanism of these drugs remains unclear. In the current study, we used MM cell lines as a model to investigate the molecular mechanism of thalidomide and to compare its potency with IMiDs such as pomalidomide. We determined that thalidomide did not inhibit cell proliferation of RPMI8226 and U266 MM cells, whereas pomalidomide showed a significant inhibitory effect on these two MM cell lines. Interestingly, we further demonstrated that although thalidomide down-regulated bFGF translation through the inhibition of IRES even at 0.1 µg/ml, pomalidomide did not have a similar affect bFGF levels. A colony formation assay demonstrated that thalidomide and the bFGF knock-down clones caused a significant reduction in the clonogenic ability of MM cells, and treatment with exogenous bFGF can recover the clonogenic ability of thalidomide-treated cells and knock-down clones, but not that of pomalidomide-treated cells. This implies that thalidomide, but not pomalidomide, targets the IRES of FGF-2.
In conclusion, our results highlight a non-cytotoxic anticancer drug target for thalidomide, the IRES of bFGF, and provide the mechanistic rationale for developing IMiDs as anti-cancer therapeutics in MM patients, with improved potency and fewer side effects
oncotarget Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .
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“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was published back in 2018 by Oncotarget and completed by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
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