Journal
ONCOTARGETS AND THERAPY
Volume 13, Issue -, Pages 1661-1676Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S224866
Keywords
aPKC inhibitor; NSCLC; ubiquitination; FAK; migration
Categories
Funding
- Daniel Tanner Foundation
- Frederick H. Leonhardt Foundation
- H.O. West Foundation
- Kyrias Foundation
- Jin and Joo Lee Family Foundation
- Miami Foundation for Cancer Research, Inc.
- Yolanda and Salvatore Gigante Charitable Foundation Trust
- Bennack-Polan Foundation
- Michael Carlisle Charitable Trust 2
- Gackstatter Foundation
- Arthur T. Cantwell Charitable Trust
- Marion E. Jerome Foundation, Inc
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Purpose: The options for treating lung cancers are limited, as diagnosis typically occurs during the late stages of the disease. There is a dire need to develop aPKC (atypical Protein Kinase C) inhibitors due to aPKC overexpression and contributions to lung cancer malignancies. In this study, we investigate the role of atypical PKCs (aPKCs) in cell proliferation and migration in lung cancer cell lines and the effect of the novel aPKC inhibitor DNDA (3,4-amino-2,7 napthalene disulfonic acid). Methods: The normal and lung cancer cells were treated with various concentrations of DNDA. We used a WST assay to determine lung cell viability, then analyzed cell apoptosis through Annexin V/PI staining and flow cytometry. Immunoprecipitation determined the proteins' associations, and Western blot allowed testing of the expression of interest proteins. We also employed the UbiTest to identify the ubiquitination of the FAK. The scratch and transwell assays measured cell migration and invasion of lung cancer cells. Results: Our data from cell viability and flow cytometry showed a significant reduction in cell proliferation and induction of apoptosis with DNDA treatment in lung cancer cells, as well as no toxic effect on normal BEAS-2B lung cells. Western blot results showed that the phosphorylation of PKC-iota and phosphorylation of FAK decreased in A549 lung cancer cells upon DNDA treatment. Immunoprecipitation (IP) data revealed an association of PKC-iota with FAK and FAK with Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b). UbiTest results suggest that PKC-iota regulates FAK cleavage through its ubiquitination by Cbl-b, thereby inhibiting A549 lung cancer cells' migration. This was evident from scratch, invasion, and migration assays. Conclusion: Our study data suggest that DNDA inhibits cell proliferation and induces apoptosis in lung cancer cells. Moreover, DNDA inhibit A549 lung cancer cells' migration by PKC-iota/FAK ubiquitination via Cbl-b.
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