Abstract
Arenobufagin, an active component isolated from the traditional Chinese medicine Chan Su, exhibits anticancer influences in several human malignancies. However, the effects and action mechanisms of arenobufagin on non-small-cell lung cancer (NSCLC) are still unknown. In this study, we reported that arenobufagin acted through activation of Noxa-related pathways and promoted apoptotic cell death in human NSCLC cells. Our results revealed that arenobufagin-induced apoptosis was caspase-dependent, as evidenced by the fact that caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) were cleaved, and pretreatment with a pan-caspase inhibitor Z-VAD-FMK inhibited the pro-apoptosis effect of arenobufagin. Mechanistically, we further found that arenobufagin rapidly upregulated the expression of the pro-apoptosis protein Noxa, and abrogated the anti-apoptosis protein Mcl-1, a major binding partner of Noxa in the cell. More importantly, the knockdown of Noxa greatly blocked arenobufagin-induced cell death, highlighting the contribution of this protein in the anti-NSCLC effects of arenobufagin. Interestingly, arenobufagin also increased the expression of p53, a direct transcriptional activator for the upregulation of the Noxa protein. Taken together, our results suggest that arenobufagin is a potential anti-NSCLC agent that triggers apoptotic cell death in NSCLC cells through interfering with the Noxa-related pathway.
Keywords:
Mcl-1; Noxa; arenobufagin; non-small-cell lung cancer; p53.
MeSH terms
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A549 Cells
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Amino Acid Chloromethyl Ketones / pharmacology
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Amphibian Venoms / chemistry
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Antineoplastic Agents / isolation & purification
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Bufanolides / chemistry*
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Bufanolides / isolation & purification
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Bufanolides / pharmacology*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Caspase 9 / genetics
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Caspase 9 / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Gene Expression Regulation, Neoplastic*
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Humans
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Medicine, Chinese Traditional
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Respiratory Mucosa / drug effects
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / pathology
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Signal Transduction
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Tumor Suppressor Protein p53 / agonists
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Amino Acid Chloromethyl Ketones
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Amphibian Venoms
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Antineoplastic Agents
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Bufanolides
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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PMAIP1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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chan su
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arenobufagin
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Poly(ADP-ribose) Polymerases
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CASP3 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 9