RRC ID 65834
Author Fujiwara D, Tsubaki M, Takeda T, Tomonari Y, Koumoto YI, Sakaguchi K, Nishida S.
Title Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells.
Journal Tumour Biol
Abstract Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.
Volume 39(10)
Pages 1010428317734947
Published 2017-10-1
DOI 10.1177/1010428317734947
PMID 28990465
MeSH Antineoplastic Agents / pharmacology* Apoptosis / drug effects* Bcl-2-Like Protein 11 / drug effects Bcl-2-Like Protein 11 / metabolism Blotting, Western Cell Line, Tumor Cell Proliferation / drug effects Hematologic Neoplasms / metabolism* Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology* Immunoprecipitation Proliferating Cell Nuclear Antigen / drug effects Proliferating Cell Nuclear Antigen / metabolism Signal Transduction / drug effects* ras Proteins / drug effects ras Proteins / metabolism
IF 3.65
Human and Animal Cells HL60(RCB0041) U937