Abstract
Camptothecin (CPT) is an effective chemotherapeutic agent for treatment of patients with cancer. The mechanisms underlying CPT-mediated responses in cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug sensitivity. However, the interaction between camptothecin and miRNA has not been previously explored. In this study, we verified that miR-125b was down-regulated in CPT-induced apoptosis in cancer cells and that ectopic expression of miR-125b partially restored cell viability and inhibited cell apoptosis that was induced by CPT. In addition, we demonstrated that CPT induced apoptosis in cancer cells by miR-125b-mediated mitochondrial pathways via targeting to the 3′-untranslated (UTR) regions of Bak1, Mcl1, and p53. A significant increase in Bak1, Mcl1, and p53 protein levels was detected in response to the treatments of CPT. It is noteworthy that the expression levels of Bak1, Mcl1, and p53 increased in a time-dependent manner and negatively correlated with miR-125b expression. It is noteworthy that we revealed that miR-125b directly targeted the 3′UTR regions of multiple genes in a CPT-induced mitochondrial pathway. In addition, most targets of miR-125b were proapoptotic genes, whereas some of the targets were antiapoptotic genes. We hypothesized that miR-125b may mediate the activity of chemotherapeutic agents to induce apoptosis by regulating multiple targets. This is the first report to show that camptothecin induces cancer cell apoptosis via miRNA-mediated mitochondrial pathways. The results suggest that suppression of miR-125b may be a novel approach for the treatment of cancer.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Science and Technology Department [Grants 2011CBA01105, 2011CB811301, 2009ZX09103-641], the National Natural Science Foundation of China [Grants 30872784, 30872297], and “the Fundamental Research Funds for the Central Universities.”
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- CPT
- camptothecin
- CPT
- camptothecin
- miRNA or miR
- microRNA
- qRT-PCR
- quantitative real-time-polymerase chain reaction
- siRNA
- small interfering RNA
- wt
- wild type
- UTR
- untranslated region
- MRE
- miRNA response element
- NC
- negative control.
- Received November 15, 2011.
- Accepted January 17, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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