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Antisense oligonucleotides against aldehyde dehydrogenase 3 inhibit hepatoma cell proliferation by affecting MAP
Giuliana Muzio1, Antonella Trombetta, Germana Martinasso
1Dipartimento di Medicina ed Oncologia Sperimentale, Università di Torino, Corso Raffaello 30, 10125, Torino, Italy. giuliana.muzio@unito.it
Abstract:
The increased activity of enzymes that eliminate anti-tumour drugs or their metabolites is one of the important limiting factors in therapeutic protocols. Among these enzymes, aldehyde dehydrogenase 3 (ALDH3) is considered a mechanism by which tumour cells evade the cytotoxic effects exerted by cyclophosphamide and drugs acting by free radical generation. It is also important in metabolising cytostatic aldehydes derived from lipid peroxidation. Therefore, ALDH3 may play a role in regulating cell proliferation in tumour cells with high activity of this enzyme. We previously reported that antisense oligonucleotides (AS-ODN) against ALDH3 strongly inhibit hepatoma cell growth, suggesting that this effect could be due to the accumulation of cytostatic aldehydes in the cells. In this research we demonstrate that AS-ODN against ALDH3 increase the quantity of malondialdehyde in the cells, and inhibit cell proliferation by affecting the MAPK pathway: a reduction of pRaf-1 and pERK1,2 was observed. These results confirm the importance of aldehydes derived from lipid peroxidation and of ALDH3 in regulating hepatoma proliferation. Moreover, the results indicate the use of AS-ODN against ALDH3 as a possible strategy to reduce growth in tumours overexpressing this enzyme.
Insights
Antisense oligonucleotides (AS-ODN) targeting aldehyde dehydrogenase 3 (ALDH3) increase harmful aldehydes in hepatoma cells. This inhibits cancer cell proliferation by impacting the MAPK pathway, suggesting a novel therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Enzyme activity influencing anti-tumour drug efficacy is a key factor in cancer therapy.
- Aldehyde dehydrogenase 3 (ALDH3) aids tumor cells in evading cytotoxic drugs and metabolizes lipid peroxidation products.
- High ALDH3 activity may regulate proliferation in tumor cells.
Purpose of the Study:
- To investigate the role of ALDH3 in hepatoma cell proliferation.
- To explore the mechanism by which antisense oligonucleotides (AS-ODN) against ALDH3 inhibit hepatoma cell growth.
- To determine the impact of ALDH3 inhibition on lipid peroxidation and cell signaling pathways.
Main Methods:
- Treatment of hepatoma cells with AS-ODN targeting ALDH3.
- Measurement of malondialdehyde levels to assess lipid peroxidation.
- Analysis of MAPK pathway components, including pRaf-1 and pERK1,2.
Main Results:
- AS-ODN against ALDH3 significantly increased malondialdehyde levels in hepatoma cells.
- Inhibition of cell proliferation was observed following ALDH3 targeting.
- A reduction in the phosphorylation of Raf-1 and ERK1,2 (pRaf-1 and pERK1,2) indicated MAPK pathway modulation.
Conclusions:
- Aldehydes from lipid peroxidation and ALDH3 are crucial regulators of hepatoma cell proliferation.
- AS-ODN targeting ALDH3 represents a potential therapeutic approach for tumors overexpressing this enzyme.
- Inhibition of ALDH3 impacts tumor growth via the MAPK signaling pathway.