Dataset Information

FK228 sensitizes radioresistant small cell lung cancer cells to radiation.

ABSTRACT:

Background

Concurrent thoracic radiation plus chemotherapy is the mainstay of first-line treatment for limited-stage small cell lung cancer (LS-SCLC). Despite initial high responsiveness to combined chemo- and radiotherapy, SCLC almost invariably relapses and develops resistance within one year, leading to poor prognosis in patients with LS-SCLC. Developing new chemical agents that increase ionizing radiation's cytotoxicity against SCLC is urgently needed.

Results

Dual histone deacetylase (HDAC) and PI3K inhibitor FK228 not only displayed potent anticancer activity, but also enhanced the therapeutic effects of radiotherapy in SCLC cells. Mechanistically, radioresistant SCLC cells exhibit a lower level of histone H3K9 acetylation and a higher expression level of the MRE11-RAD50-NBS1 (MRN) complex and show more efficient and redundant DNA damage repair capacities than radiosensitive SCLC cells. FK228 pretreatment resulted in marked induction of H3k9 acetylation, attenuated homologous recombination (HR) repair competency and impaired non-homologous end joining (NHEJ) repair efficacy, leading to the accumulation of radiation-induced DNA damage and radiosensitization.

Conclusion

The study uncovered that FK228 sensitized human radioresistant SCLC cells to radiation mainly through induction of chromatin decondensation and suppression of DNA damage signaling and repair. Our study provides a rational basis for a further clinical study to test the potential of FK228 as a radiosensitizing agent to increase the radiation-induced tumor cell kill in LS-SCLC patients.

SUBMITTER: Li H

PROVIDER: S-EPMC7905898 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

FK228 sensitizes radioresistant small cell lung cancer cells to radiation.

Li Hong H Ma Liying L Bian Xing X Lv Yang Y Lin Wenchu W

Clinical epigenetics 20210225 1

<h4>Background</h4>Concurrent thoracic radiation plus chemotherapy is the mainstay of first-line treatment for limited-stage small cell lung cancer (LS-SCLC). Despite initial high responsiveness to combined chemo- and radiotherapy, SCLC almost invariably relapses and develops resistance within one year, leading to poor prognosis in patients with LS-SCLC. Developing new chemical agents that increase ionizing radiation's cytotoxicity against SCLC is urgently needed.<h4>Results</h4>Dual histone dea ...[more]

PMID: 33632300

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Project description:Pancreatic ductal adenocarcinoma is one of the most aggressive cancer types and is well-known for its general low intrinsic radiosensitivity. In order to resolve mechanisms of how PDAC cells carry out radioresistance, a combination of proteomics and phosphoproteomics of two radiosensitive as well as radioresistant murine PDAC cell lines upon exposition to radiation was performed. A high depth of (phospho)proteomic identifications with > 13000 confidently identified phosphorylation sites and > 7800 proteins was achieved. Measuring the response of the phosphoproteome upon radiation revealed >700 phosphorylation sites on >400 proteins which were regulated in all four cell lines independently of the sensitivity status. This analysis validated already known radiomarkers but also uncovered novel members of the radiation-dependent signaling network in PDAC cells that were shown to be exclusively based on protein phosphorylation but not protein expression. Among those radioresponsive phosphoproteins were ten novel ATM substrates, which were validated by in vitro kinase assays. Comparison of radiosensitive and -resistant cells revealed a complex regulation of apoptotic processes, while changes in expression of DNA repair proteins seemed to not play a pivotal role. Especially increased expression of NQO1 was found to be a potential mechanism enabling resistance by clearing harmful reactive oxygen species from the PDAC cells. Further analysis of the radioresistance-associated-phosphoproteome, which was especially enriched in phosphoproteins with cytoskeleton organizational function, uncovered increased Actin dynamics and FAK activity in radioresistant cells. Both likely lead to increased survival, migrational capacity and perturbations in chromatin condensation which could oppose radiation. Based on the displayed adaptions in cellular protein expression and signaling in resistant PDAC cells, pharmacological inhibition of NQO1 and FAK could be suggested to sensitize towards radiation.

Dataset Information

FK228 sensitizes radioresistant small cell lung cancer cells to radiation.

Background

Results

Conclusion

Publications

FK228 sensitizes radioresistant small cell lung cancer cells to radiation.

Similar Datasets

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