Cyclin-Dependent Kinase Inhibitor BMI-1026 Induces Apoptosis by Downregulating Mcl-1 (L) and c-FLIP (L) and Inactivating p-Akt in Human Renal Carcinoma Cells

Autor: Shin Kim, Hyunsu Kang, Taeg Kyu Kwon, Yu Ri Nam, Dong-Eun Kim, Jong-Wook Park, Jinho Lee, Ki-Suk Kim
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
CASP8 and FADD-Like Apoptosis Regulating Protein
cellular FADD-like IL-1β-converting enzyme inhibitory protein
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
0302 clinical medicine
LY294002
Biology (General)
Spectroscopy
biology
Kinase
apoptosis
General Medicine
Flow Cytometry
Computer Science Applications
XIAP
Chemistry
030220 oncology & carcinogenesis
QH301-705.5
Morpholines
Blotting
Western
Down-Regulation
p-Akt
Inhibitor of apoptosis
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Phenols
Cyclin-dependent kinase
Cell Line
Tumor
Humans
BMI-1026
Physical and Theoretical Chemistry
Carcinoma
Renal Cell
Molecular Biology
Protein kinase B
QD1-999
PI3K/AKT/mTOR pathway
Organic Chemistry
Mcl-1
HCT116 Cells
Pyrimidines
030104 developmental biology
chemistry
Chromones
Apoptosis
Cancer research
biology.protein
Proto-Oncogene Proteins c-akt
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 4268, p 4268 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 8
ISSN: 1661-6596
1422-0067
Popis: Previous studies have investigated the inhibitory effect of BMI-1026 on cyclin-dependent kinase 1 in vitro. However, the molecular mechanisms by which BMI-1026 treatment leads to cancer cell death remain unclear. This study was conducted to investigate the anticancer mechanisms of BMI-1026 on human renal carcinoma Caki cells. BMI-1026 induced apoptosis in association with the cleavage of poly(ADP-ribose) polymerase and pro-caspase-3 and the release of apoptosis-inducing factor and cytochrome c from mitochondria in Caki cells. BMI-1026-induced apoptosis was inhibited by the pan-caspase inhibitor z-VAD-fmk. Furthermore, BMI-1026 downregulated Bcl-2 and X-linked inhibitor of apoptosis protein (XIAP) at the transcriptional level and Mcl-1 (L) and cellular FADD-like IL-1β-converting enzyme inhibitory protein (c-FLIP (L)) at the post-transcriptional level. Interestingly, Mcl-1 (L) and c-FLIP (L), but not Bcl-2 or XIAP, played important roles in BMI-1026-induced Caki cell apoptosis. Although the constitutively active form of Akt did not attenuate BMI-1026-induced apoptosis, blockade of the PI3K/Akt pathway using a subcytotoxic concentration of the PI3K/Akt inhibitor LY294002 enhanced Caki cell apoptosis induced by BMI-1026. Electrophysiological safety was confirmed by determining the cardiotoxicity of BMI-1026 via left ventricular pressure analysis. These results suggest that BMI-1026 is a potent multitarget anticancer agent with electrophysiological safety and should be further investigated.
Databáze: OpenAIRE
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