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Published on: November 11, 2014
Gene expression profiling unveils the temporal dynamics of CIGB-300-regulated transcriptome in AML cell lines
Dania Vázquez-Blomquist1, Ailyn C Ramón2, Mauro Rosales2,3
1Pharmacogenomic Group, Department of System Biology, Biomedical Research Division, Center for Genetic Engineering & Biotechnology (CIGB), 10600, Havana, Cuba. dania.vazquez@cigb.edu.cu.
Background:
Protein kinase CK2 activity is implicated in the pathogenesis of various hematological malignancies like Acute Myeloid Leukemia (AML) that remains challenging concerning treatment. This kinase has emerged as an attractive molecular target in therapeutic. Antitumoral peptide CIGB-300 blocks CK2 phospho-acceptor sites on their substrates but it also binds to CK2α catalytic subunit. Previous proteomic and phosphoproteomic experiments showed molecular and cellular processes with relevance for the peptide action in diverse AML backgrounds but earlier transcriptional level events might also support the CIGB-300 anti-leukemic effect. Here we used a Clariom S HT assay for gene expression profiling to study the molecular events supporting the anti-leukemic effect of CIGB-300 peptide on HL-60 and OCI-AML3 cell lines.
Results:
We found 183 and 802 genes appeared significantly modulated in HL-60 cells at 30 min and 3 h of incubation with CIGB-300 for p < 0.01 and FC > = │1.5│, respectively; while 221 and 332 genes appeared modulated in OCI-AML3 cells. Importantly, functional enrichment analysis evidenced that genes and transcription factors related to apoptosis, cell cycle, leukocyte differentiation, signaling by cytokines/interleukins, and NF-kB, TNF signaling pathways were significantly represented in AML cells transcriptomic profiles. The influence of CIGB-300 on these biological processes and pathways is dependent on the cellular background, in the first place, and treatment duration. Of note, the impact of the peptide on NF-kB signaling was corroborated by the quantification of selected NF-kB target genes, as well as the measurement of p50 binding activity and soluble TNF-α induction. Quantification of CSF1/M-CSF and CDKN1A/P21 by qPCR supports peptide effects on differentiation and cell cycle.
Conclusions:
We explored for the first time the temporal dynamics of the gene expression profile regulated by CIGB-300 which, along with the antiproliferative mechanism, can stimulate immune responses by increasing immunomodulatory cytokines. We provided fresh molecular clues concerning the antiproliferative effect of CIGB-300 in two relevant AML backgrounds.
Insights
The antitumoral peptide CIGB-300 modulates gene expression in Acute Myeloid Leukemia (AML) cells, impacting apoptosis, cell cycle, and immune responses. This provides new insights into CIGB-300
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Protein kinase CK2 is crucial in hematological malignancies like Acute Myeloid Leukemia (AML).
- The antitumoral peptide CIGB-300 targets CK2 activity and has shown promise in AML.
- Transcriptional events may underlie CIGB-300's anti-leukemic effects.
Purpose of the Study:
- To investigate the gene expression profile changes induced by CIGB-300 in AML cell lines.
- To understand the early transcriptional events supporting CIGB-300's anti-leukemic activity.
Main Methods:
- Gene expression profiling using Clariom S HT assay on HL-60 and OCI-AML3 cell lines.
- Functional enrichment analysis of modulated genes.
- Quantitative PCR (qPCR) for specific gene targets.
- Assays for NF-kB pathway activity and TNF-α induction.
Main Results:
- CIGB-300 significantly modulated gene expression in both AML cell lines, with distinct temporal dynamics.
- Enrichment analysis revealed impacts on apoptosis, cell cycle, differentiation, and cytokine/interleukin signaling pathways, including NF-kB and TNF signaling.
- CIGB-300's effects on NF-kB signaling and pathways related to differentiation and cell cycle were experimentally validated.
Conclusions:
- This study provides the first temporal analysis of CIGB-300-regulated gene expression in AML.
- CIGB-300 not only exhibits antiproliferative effects but may also stimulate immune responses.
- New molecular insights into CIGB-300's anti-leukemic mechanisms in AML were uncovered.
