scholarly journals IL-24 Inhibits Lung Cancer Growth by Suppressing GLI1 and Inducing DNA Damage

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1879
Author(s):  
Janani Panneerselvam ◽  
Akhil Srivastava ◽  
Meghna Mehta ◽  
Allshine Chen ◽  
Yan D. Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Hedgehog Signaling ◽  
Lung Tumor ◽  
Transcriptional Level ◽  
Aberrant Expression ◽  
Damage Response ◽  
Mrna And Protein Expression ◽  
Parp Activity ◽  
Marked Suppression

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.

scholarly journals Increased PARP Activity and DNA Damage in NSCLC Patients: The Influence of COPD

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3333
Author(s):  
Jun Tang ◽  
Víctor Curull ◽  
Xuejie Wang ◽  
Coral Ampurdanés ◽  
Xavier Duran ◽  
...  
Keyword(s):  
Dna Damage ◽  
Lung Tumor ◽  
Colorimetric Assay ◽  
Thoracoscopic Surgery ◽  
Lung Tumors ◽  
Chronic Obstructive ◽  
Activity Levels ◽  
Copd Patients ◽  
Parp Activity ◽  
Parp 1

(1) Background: Lung cancer (LC) is a major leading cause of death worldwide. Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 are key players in cancer. We aimed to assess PARP-1 and PARP-2 expression and activity and DNA damage in tumors and non-tumor lungs from patients with/without chronic obstructive pulmonary disease (COPD). (2) Methods: Lung tumor and non-tumor specimens were obtained through video-assisted thoracoscopic surgery (VATS) in LC patients with/without underlying COPD (two groups of patients, n = 15/group). PARP-1 and PARP-2 expression (ELISA), PARP activity (PARP colorimetric assay kit) and DNA damage (immunohistochemistry) levels were identified in all samples. (3) Results: Both PARP-1 and PARP-2 expression levels were significantly lower in lung tumors (irrespective of COPD)compared to non-tumor specimens, while DNA damage and PARP activity levels significantly increased in lung tumors compared to non-tumor specimens only in LC-COPD patients. PARP-2 expression was positively correlated with smoking burden in LC-COPD patients. (4) Conclusions: In lung tumors of COPD patients, an overactivation of PARP enzyme was observed. A decline in PARP-1 and PARP-2 protein expression was seen in lung tumors irrespective of COPD. Other phenotypic features (airway obstruction) beyond cancer may account for the increase in PARP activity seen in the tumors of patients with underlying COPD.

Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells

DNA Repair ◽  
2016 ◽  
Vol 37 ◽  
pp. 1-11 ◽  
Author(s):  
Raafat A. El-Awady ◽  
Mohammad H. Semreen ◽  
Maha M. Saber-Ayad ◽  
Farhan Cyprian ◽  
Varsha Menon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Lung Cancer Cells ◽  
Damage Response ◽  
Induction Of Apoptosis

scholarly journals Targeting of histone methyltransferase DOT1L plays a dual role in chemosensitization of retinoblastoma cells and enhances the efficacy of chemotherapy

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Yu Mao ◽  
Yu Sun ◽  
Zhixuan Wu ◽  
Jingzhi Zheng ◽  
Jianing Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Combined Therapy ◽  
Single Agent ◽  
Chemotherapeutic Agents ◽  
Dual Role ◽  
Aberrant Expression ◽  
Chromatin Regulators ◽  
Therapeutic Benefits ◽  
Damage Response

AbstractAberrant and exclusive expression of chromatin regulators in retinoblastoma (RB) in contrast to terminally differentiated normal retina presents a unique opportunity of selective targeting for RB. However, precise roles of these chromatin regulators in RB development and their potential as therapeutic targets have not been defined thoroughly. Here, we report that targeting of disruptor of telomeric silencing 1-like (DOT1L), a histone H3K79 methyltransferase, sensitizes RB cells to chemotherapeutic drugs by impairing the DNA damage response and thereby potentiating apoptosis while it is largely inefficacious as a single-agent therapy. Moreover, we identified high mobility group AT-hook 2 (HMGA2) as a novel DOT1L target gene in RB cells and found that its aberrant expression is dependent on DOT1L. As HMGA2 depletion reduced CHK1 phosphorylation during DNA damage response and augmented the drug sensitivity in RB cells, our results suggested that DOT1L targeting has a dual role in chemosensitization of RB cells by directly interfering with the immediate involvement of DOT1L in early DNA damage response upon genotoxic insults and also by downregulating the expression of HMGA2 as a rather late effect of DOT1L inhibition. Furthermore, we provide the first preclinical evidence demonstrating that combined therapy with a DOT1L inhibitor significantly improves the therapeutic efficacy of etoposide in murine orthotopic xenografts of RB by rendering the response to etoposide more potent and stable. Taken together, these results support the therapeutic benefits of DOT1L targeting in combination with other chemotherapeutic agents in RB, with mechanistic insights into how DOT1L targeting can improve the current chemotherapy in an RB cell-selective manner.

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