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Research article
Maha Saber-Ayad
University of Sharjah College of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9287-7621
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Background Lung cancer is the most common cancer globally. Protein arginine methyltransferase 5 (PRMT5) is identified to be involved in gene transcriptional regulation and cell division. PRMT5 is highly expressed in lung adenocarcinoma, hepatocellular carcinoma, and melanoma, raising evidence that PRMT5 might be involved in tumorigenesis. The aim of this study is to examine potential selective anti-neoplastic activity of PRMT5 inhibitor, Arginine methyltransferase inhibitor 1 (AMI-1) and cisplatin on lung adenocarcinoma.
Methods Effect of AMI-1 on PRMT5 activity inhibition in lung adenocarcinoma cell line, A549, in response to standard chemotherapeutic agent, cisplatin, was assessed. Bioinformatic analyses were carried out to identify the prognostic value of PRMT5 and its major functional pathways in lung adenocarcinoma. Cell viability, PMRT5 protein levels, extent of cell migration, survival of cancer cells, and cell cycle progression and apoptosis were examined. Drug combination was also evaluated in human bronchial epithelial cells (HBEpC).
Results Bioinformatics identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5 associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival. Combination treatment with 10 µM AMI-1 and of Cisplatin significantly reduced viable cell percentages. Cell cycle arrest in A549 cells was evident after AMI-1, which was reinforced after combination treatment. Apoptosis was observed after treatment with both drugs. Western blot analysis showed reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on normal epithelial cells. Finally, treatment with both drugs led to a decreased cell migration rate.
Conclusions This study highlights evidence of novel selective antitumor additive activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells. Survival of normal bronchial epithelial cells was not affected by using AMI-1.
Keywords
PRMT5, lung adenocarcinoma, epigenetics, cisplatin, histone, HBEpC
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Maha Saber-Ayad
University of Sharjah College of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9287-7621
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 24 Feb, 2020
No community comments so far
Editorial decision: Major revision
On 28 Apr, 2020
Review #4 received
Received 27 Apr, 2020
Review #3 received
Received 27 Apr, 2020
Reviewer #4 agreed
On 08 Apr, 2020
Reviewer #2 agreed
On 05 Apr, 2020
Reviewer #3 agreed
On 05 Apr, 2020
Review #2 received
Received 05 Apr, 2020
Review #1 received
Received 20 Mar, 2020
Reviewers invited
Invitations sent on 05 Mar, 2020
Reviewer #1 agreed
On 05 Mar, 2020
Editor assigned
On 19 Feb, 2020
Submission checks complete
On 18 Feb, 2020
Editor invited
On 18 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background Lung cancer is the most common cancer globally. Protein arginine methyltransferase 5 (PRMT5) is identified to be involved in gene transcriptional regulation and cell division. PRMT5 is highly expressed in lung adenocarcinoma, hepatocellular carcinoma, and melanoma, raising evidence that PRMT5 might be involved in tumorigenesis. The aim of this study is to examine potential selective anti-neoplastic activity of PRMT5 inhibitor, Arginine methyltransferase inhibitor 1 (AMI-1) and cisplatin on lung adenocarcinoma.
Methods Effect of AMI-1 on PRMT5 activity inhibition in lung adenocarcinoma cell line, A549, in response to standard chemotherapeutic agent, cisplatin, was assessed. Bioinformatic analyses were carried out to identify the prognostic value of PRMT5 and its major functional pathways in lung adenocarcinoma. Cell viability, PMRT5 protein levels, extent of cell migration, survival of cancer cells, and cell cycle progression and apoptosis were examined. Drug combination was also evaluated in human bronchial epithelial cells (HBEpC).
Results Bioinformatics identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5 associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival. Combination treatment with 10 µM AMI-1 and of Cisplatin significantly reduced viable cell percentages. Cell cycle arrest in A549 cells was evident after AMI-1, which was reinforced after combination treatment. Apoptosis was observed after treatment with both drugs. Western blot analysis showed reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on normal epithelial cells. Finally, treatment with both drugs led to a decreased cell migration rate.
Conclusions This study highlights evidence of novel selective antitumor additive activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells. Survival of normal bronchial epithelial cells was not affected by using AMI-1.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
This is a list of supplementary files associated with this preprint. Click to download.
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