Abstract
KRIBB11, an HSF1 inhibitor, was shown to sensitize various types of cancer cells to treatment with several anticancer drugs. However, the exclusive effects of KRIBB11 in preventing the growth of glioblastoma cells and the related mechanisms have not been elucidated yet. Herein, we aimed to examine the potential of KRIBB11 as an anticancer agent for glioblastoma. Using MTT and colony formation assays and Western blotting for c-PARP, we demonstrated that KRIBB11 substantially inhibits the growth of A172 glioma cells by inducing apoptosis. At the molecular level, KRIBB11 decreased anti-apoptotic protein MCL-1 levels, which was attributable to the increase in MULE ubiquitin ligase levels. However, the constitutive activity of HSF1 in A172 cells was not influenced by the exclusive treatment with KRIBB11. Additionally, based on cycloheximide chase assay, we found that KRIBB11 markedly retarded the degradation of MULE. In conclusion, stabilization of MULE upon KRIBB11 treatment is apparently an essential step for degradation of MCL-1 and the subsequent induction of apoptosis in A172 cells. Our results have expanded the knowledge on molecular pathways controlled by KRIBB11 and could be potentially effective for developing an inhibitory therapeutic strategy for glioblastoma.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive and frequently occurring primary brain tumor with a median survival of less than 1 year [1]
Our results revealed that the KRIBB11-induced MCL-1 decrease is attributable to induction of MULE ubiquitin ligase at protein levels, which suggests the involvement of KRIBB11 in the regulation of MULE protein stability
We demonstrated that an exclusive treatment with KRIBB11 effectively induces apoptosis in A172 glioma cells through acceleration of MCL-1 degradation, which is not accompanied by any alteration of HSF1 activity
Summary
Glioblastoma multiforme (GBM) is the most aggressive and frequently occurring primary brain tumor with a median survival of less than 1 year [1]. The combined treatment with an AKT inhibitor and KRIBB11 exhibited synergistic effects in the suppression of breast cancer cell growth of different subtypes in vitro and in vivo [9]. A probable molecular basis for KRIBB11 priming cancer cells to apoptosis could include reduced expression of HSF1 target genes; this is apparently a potential mechanism, because the sensitizing effects of KRIBB11 were reproduced upon HSF1 silencing [7,8,9]. Considering that the high expression of HSF1 in various types of cancers are frequently associated with poor prognosis and resistance for chemotherapy [11], the sensitizing effects of KRIBB11 on the suppression of cancer cell growth appear to be a promising therapeutic strategy for clinical application
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