Dataset Information

Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration.

ABSTRACT: Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin retards the same. A search for the underlying mechanism revealed that aspirin pre-treatment abrogates p300 binding both at TATA-box and initiator (INR) regions of mTOR promoter of CSCs, thereby impeding RNA polymerase II binding at those sites and repressing mTOR gene transcription. As a consequence of mTOR down-regulation, Akt is deactivated via dephosphorylation at Ser⁴⁷³ residue thereby activating Gsk3? that in turn causes destabilization of Snail and ?-catenin, thus reverting epithelial to mesenchymal transition (EMT). However, alone aspirin fails to hinder migration since it does not inhibit the Integrin/Fak pathway, which is highly activated in NSCLC stem cells. On the other hand, in aspirin pre-treated CSCs, cisplatin stalls migration by hindering the integrin pathway. These results signify the efficacy of aspirin in sensitizing NSCLC stem cells towards the anti-migration effect of cisplatin. Cumulatively, our findings raise the possibility that aspirin might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to impede migration of NSCLC stem cells otherwise. This may consequently lead to the advancement of remedial outcome for the metastatic NSCLCs.

SUBMITTER: Khan P

PROVIDER: S-EPMC6858356 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration.

Khan Poulami P Bhattacharya Apoorva A Sengupta Debomita D Banerjee Shruti S Adhikary Arghya A Das Tanya T

Scientific reports 20191115 1

Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin ret ...[more]

PMID: 31729456

Similar Datasets

Project description:BackgroundOvarian cancer is the most common gynecological malignancy and is difficult to manage due to the emergence of resistance to various chemotherapeutic drugs. New efforts are urgently awaited. Aspirin, which is traditionally considered a nonsteroidal anti-inflammatory drug (NSAID), has been reported to exert potential chemopreventive effects. Therefore, we aimed to investigate the anticancer effect and explore the underlying molecular mechanisms of aspirin on epithelial ovarian cancer (EOC) cells.MethodsWe conducted wound healing, transwell migration, EdU cell proliferation, colony formation and apoptosis detection assays to observe the effects of aspirin on the migration, proliferation and apoptosis of EOC cells (A2870, Caov-3, and SK-OV-3). EOC cells were treated with a combination of aspirin and cisplatin (CDDP) to observe the effect of aspirin on enhancing CDDP sensitivity. Orthotopic xenograft models of ovarian cancer established with A2780-Luciferase-GFP cells were applied to compare tumor growth inhibition in the control, CDDP and CDDP plus aspirin groups through in vivo imaging, which can be used to continuously monitor tumor growth. The expression and acetylation levels of p53 in EOC cells treated with aspirin were determined using western blotting, and p53 acetylation levels were examined in tumors harvested from the transplanted mice. Quantitative real-time PCR was used to assess the mRNA expression of p53 target genes.ResultsAspirin inhibited migration and proliferation and induced apoptosis in EOC cell lines in a concentration-dependent manner. In vitro, aspirin enhanced the sensitivity of EOC cells to CDDP by increasing its inhibitory effect on proliferation and its effect on inducing apoptosis. In vivo, the differences in the tumor growth inhibition rates among the different CDDP experimental groups were statistically significant (p < 0.05). Aspirin did not affect p53 protein expression but increased the p53 acetylation level in a concentration-dependent manner. In addition, the mRNA levels of CDKN1A, BAX, FOXF1, PUMA, and RRAD in EOC cells were significantly increased by the aspirin treatment.ConclusionsAspirin inhibits tumor progression and enhances the CDDP sensitivity of EOC cells. These antitumor effects of aspirin might be mediated by p53 acetylation and subsequent activation of p53 target genes.

Project description:Laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC) are two types of head and neck cancers with high incidence rates and relatively poor prognoses. The aim of the present study was to determine the effects of microRNA (miR/miRNA)-136-5p and its downstream target, Rho-associated coiled-coil containing protein kinase 1 (ROCK1), on LSCC and HPSCC progression and cisplatin sensitivity. The miRNA and protein expression levels in head and neck cancer cell lines were evaluated using reverse transcription-quantitative PCR and western blotting, respectively. MTT, wound healing assays, transwell assays and flow cytometry analysis were performed to measure cell properties. The binding between miR-136-5p and ROCK1 was detected using a dual-luciferase reporter assay. Autophagy double-labeled adenoviral infection assays were used to assess cell autophagy. The results showed that miR-136-5p was expressed in LSCC and HPSCC cells. Functional experiments showed that the expression of miR-136-5p in LSCC and HPSCC cells was negatively correlated with cell viability, invasion and migration. Additionally, miR-136-5p overexpression inhibited epithelial-mesenchymal transition, whereas miR-136-5p knockdown had the opposite effect. Dual-luciferase reporter assays confirmed the targeting relationship between miR-136-5p and ROCK1. miR-136-5p overexpression increased the cisplatin sensitivity of LSCC and HPSCC cells by reducing cell viability, as well as promoting cell apoptosis and autophagy. miR-136-5p overexpression decreased the expression levels of its downstream target ROCK1 and attenuated activity of the Akt/mTOR signaling pathway in cisplatin-treated LSCC and HPSCC cells. Conversely, miR-136-5p knockdown increased ROCK1 levels and decreased cisplatin sensitivity of the LSCC and HPSCC cells by increasing cell viability and inhibiting cell apoptosis, which was reversed by ROCK1 inhibition using the ROCK1 inhibitor, Y27632. Taken together, the results showed that the miR-136-5p/ROCK1 axis inhibits cell invasion and migration, and increases the sensitivity of LSCC and HPSCC cells to cisplatin.

Project description:BackgroundEpithelial ovarian cancer (OC) is the fourth leading cause of cancer-related deaths in women, with a 5-year survival rate of 30%-50%. Platinum resistance is the chief culprit for the high recurrence and mortality rates. Several studies confirm that the metabolic regulation of ubiquitinating enzymes plays a vital role in platinum resistance in OC.MethodsIn this study, we selected ubiquitin-conjugating enzyme E2S (UBE2S) as the candidate gene for validation. The levels of UBE2S expression were investigated using TCGA, GTEx, UALCAN, and HPA databases. In addition, the correlation between UBE2S and platinum resistance in OC was analyzed using data from TCGA. Cisplatin-resistant OC cell lines were generated and UBE2S was knocked down; the transfection efficiency was verified. Subsequently, the effects of knockdown of UBE2S on the proliferation and migration of cisplatin-resistant OC cells were examined through the CCK8, Ki-67 immunofluorescence, clone formation, wound healing, and transwell assays. In addition, the UBE2S gene was also validated in vivo by xenograft models in nude mice. Finally, the relationship between the UBE2S gene and autophagy and the possible underlying regulatory mechanism was preliminarily investigated through MDC and GFP-LC3-B autophagy detection and western blotting experiments. Most importantly, experimental validation of mTOR agonist reversion (the rescuse experiments) was also performed.ResultsUBE2S was highly expressed in OC at both nucleic acid and protein levels. The results of immunohistochemistry showed that the level of UBE2S expression in platinum-resistant samples was significantly higher relative to the platinum-sensitive samples. By cell transfection experiments, knocking down of the UBE2S gene was found to inhibit the proliferation and migration of cisplatin-resistant OC cells. Moreover, the UBE2S gene could inhibit autophagy by activating the PI3K/AKT/mTOR signaling pathway to induce cisplatin resistance in OC in vivo and in vitro.ConclusionIn conclusion, we discovered a novel oncogene, UBE2S, which was associated with platinum response in OC, and examined its key role through bioinformatics and preliminary experiments. The findings may open up a new avenue for the evaluation and treatment of OC patients at high risk of cisplatin resistance.

Dataset Information

Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration.

Publications

Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets