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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
miR-181a and miR-630 regulate cisplatin-induced cancer cell death
Lorenzo Galluzzi1, Eugenia Morselli, Ilio Vitale
1Institut National de la Sante et de la Recherche Medicale, U848, Villejuif, France.
Abstract:
MicroRNAs (miRNA) are noncoding RNAs that regulate multiple cellular processes, including proliferation and apoptosis. We used microarray technology to identify miRNAs that were upregulated by non-small cell lung cancer (NSCLC) A549 cells in response to cisplatin (CDDP). The corresponding synthetic miRNA precursors (pre-miRNAs) per se were not lethal when transfected into A549 cells yet affected cell death induction by CDDP, C2-ceramide, cadmium, etoposide, and mitoxantrone in an inducer-specific fashion. Whereas synthetic miRNA inhibitors (anti-miRNAs) targeting miR-181a and miR-630 failed to modulate the response of A549 to CDDP, pre-miR-181a and pre-miR-630 enhanced and reduced CDDP-triggered cell death, respectively. Pre-miR-181a and pre-miR-630 consistently modulated mitochondrial/postmitochondrial steps of the intrinsic pathway of apoptosis, including Bax oligomerization, mitochondrial transmembrane potential dissipation, and the proteolytic maturation of caspase-9 and caspase-3. In addition, pre-miR-630 blocked early manifestations of the DNA damage response, including the phosphorylation of the ataxia-telangiectasia mutated (ATM) kinase and of two ATM substrates, histone H2AX and p53. Pharmacologic and genetic inhibition of p53 corroborated the hypothesis that pre-miR-630 (but not pre-miR-181a) blocks the upstream signaling pathways that are ignited by DNA damage and converge on p53 activation. Pre-miR-630 arrested A549 cells in the G0-G1 phase of the cell cycle, correlating with increased levels of the cell cycle inhibitor p27(Kip1) as well as with reduced proliferation rates and resulting in greatly diminished sensitivity of A549 cells to the late S-G2-M cell cycle arrest mediated by CDDP. Altogether, these results identify miR-181a and miR-630 as novel modulators of the CDDP response in NSCLC.
Insights
MicroRNAs (miRNAs) regulate cell death in non-small cell lung cancer (NSCLC). miR-181a enhances cisplatin-induced cell death, while miR-630 reduces it by blocking DNA damage response and cell cycle arrest.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- MicroRNAs (miRNAs) are key regulators of cellular processes, including proliferation and apoptosis.
- Non-small cell lung cancer (NSCLC) exhibits complex responses to chemotherapy, involving intricate regulatory networks.
- Understanding miRNA involvement in chemoresistance is crucial for developing targeted therapies.
Purpose of the Study:
- To identify specific miRNAs upregulated in NSCLC cells treated with cisplatin (CDDP).
- To investigate the functional role of identified miRNAs (miR-181a and miR-630) in modulating CDDP-induced apoptosis and DNA damage response.
- To elucidate the mechanisms by which these miRNAs affect cancer cell sensitivity to chemotherapy.
Main Methods:
- Microarray analysis to identify differentially expressed miRNAs in A549 NSCLC cells upon CDDP treatment.
- Transfection of synthetic miRNA precursors (pre-miRNAs) and inhibitors (anti-miRNAs) into A549 cells.
- Assessment of cell death induction by various chemotherapeutic agents.
- Analysis of apoptosis pathway components (Bax, caspase-9, caspase-3) and DNA damage response markers (ATM, H2AX, p53).
- Cell cycle analysis and assessment of cell cycle inhibitors (p27Kip1).
Main Results:
- Upregulation of specific miRNAs, including miR-181a and miR-630, in CDDP-treated NSCLC cells.
- Pre-miR-181a enhanced CDDP-induced cell death, whereas pre-miR-630 reduced it.
- Both miRNAs modulated mitochondrial apoptosis pathways.
- Pre-miR-630 inhibited DNA damage response signaling (ATM/p53) and caused G0-G1 cell cycle arrest, reducing sensitivity to CDDP.
- Pre-miR-630's effects were linked to p53 activation pathways.
Conclusions:
- miR-181a and miR-630 are novel modulators of cisplatin response in NSCLC.
- miR-181a promotes CDDP-induced apoptosis, while miR-630 confers resistance by interfering with DNA damage response and cell cycle progression.
- These findings highlight the potential of targeting specific miRNAs for overcoming chemoresistance in NSCLC.
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