Abstract
Aberrant expression of GLI1 is responsible for aggressive tumor behavior and survival due to its effects on the DNA damage response (DDR). We investigated whether interleukin (IL)-24, a tumor suppressor, inhibits GLI1 and the associated DDR pathway in human NSCLCs. IL-24 treatment reduces mRNA and protein expression of GLI1 in lung tumor cells, but not in normal cells. GLI1 reporter assay and mRNA studies demonstrated that IL-24 regulates GLI1 at the post-transcriptional level by favoring mRNA degradation. Associated with GLI1 inhibition was marked suppression of the ATM-mediated DDR pathway resulting in increased DNA damage, as evidenced by γ-H2AX foci and Comet assay. Furthermore, attenuation of GLI1-associated DDR by IL-24 increased caspase-3 and PARP activity, resulting in cancer cell apoptosis. GLI1 inhibition and overexpression confirmed that IL-24-mediated anti-tumor effects involved the GLI-dependent pathway. Finally, we observed that IL-24-mediated alteration in GLI1 is independent of the canonical hedgehog-signaling pathway. Our study provides evidence that IL-24 treatment induces DNA damage, and reduces GLI1 expression and offers an opportunity for testing IL-24-based therapy for inhibiting GLI1 in lung cancer.
Highlights
Lung cancer remains the leading cause of cancer-related death worldwide, despite extensive advances made in treatment approaches [1,2,3,4,5]
To assess whether Glioma-associated oncogene homolog 1 (GLI1) plays a role in lung adenocarcinoma, we generated a GLI1 gene expression dataset from the TCGA Lung Adenocarcinoma (LUAD) database of 577 patients
A significant increase in GLI1 mRNA expression was observed in stage II but not in stage III when compared to stage I disease (p < 0.013)
Summary
Lung cancer remains the leading cause of cancer-related death worldwide, despite extensive advances made in treatment approaches [1,2,3,4,5]. Drug resistance and metastasis make effective treatment strategies difficult [6]. Several ongoing studies into the molecular basis of lung cancer have shown that various signaling pathways are deregulated during the tumorigenic process and are involved in the resistance of cancer cells to existing therapies [7]. Novel biological therapies targeting oncogenic signaling pathways that initiate andeffectively kill tumor cells will improve the overall survival of patients with lung cancer. Aberrant activation and deregulation of SHH signaling lead to tumor initiation and progression, and Cancers 2019, 11, 1879; doi:10.3390/cancers11121879 www.mdpi.com/journal/cancers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
