Abstract
Simple SummaryRadiomimetic drugs induce extensive genotoxic insults to their target cells. Irreparable DNA damage leaves cells with the choice between a program leading to cell death or senescence, but not DNA repair. Among the challenges of an advanced stage of small cell lung carcinoma (SCLC), the resistance to radiomimetic drugs is the most prominent one. In SCLC, the initial chemotherapeutic treatment primes cell to modify their DNA repair and cell cycle regulatory systems, using alternative but highly efficient forms of DNA repair and auxiliary factors. This modulated system now bypasses several regulatory controls. Thus, at this stage, cells become resistant to any beneficial effects of chemotherapeutic drugs. In the present study, we observed that variant-V of the receptor for advanced glycation end-products (RAGE) is abundantly expressed in advancing and metastasizing SCLC. Therefore, it may serve as a potential target for specific therapeutic interventions directed to SCLC.Small cell lung carcinoma (SCLC) is a highly aggressive malignancy with a very high mortality rate. A prominent part of this is because these carcinomas are refractory to chemotherapies, such as etoposide or cisplatin, making effective treatment almost impossible. Here, we report that elevated expression of the RAGE variant-V in SCLC promotes homology-directed DNA DSBs repair when challenged with anti-cancer drugs. This variant exclusively localizes to the nucleus, interacts with members of the double-strand break (DSB) repair machinery and thus promotes the recruitment of DSBs repair factors at the site of damage. Increased expression of this variant thus, promotes timely DNA repair. Congruently, the tumor cells expressing high levels of variant-V can tolerate chemotherapeutic drug treatment better than the RAGE depleted cells. Our findings reveal a yet undisclosed role of the RAGE variant-V in the homology-directed DNA repair. This variant thus can be a potential target to be considered for future therapeutic approaches in advanced SSLC.
Highlights
Small cell lung carcinoma (SCLC) represents one of the most aggressive and lethal forms of lung cancer [1]
To determine the functional importance of these splice variants, comparative sequence-based in silico analysis of both human RAGEWT and RAGE variant-V was performed
It was observed that variant of RAGE (vRAGE) retains the N-terWT including the DNA binding region and the predicted epigenetic reguminus of RAGE
Summary
Small cell lung carcinoma (SCLC) represents one of the most aggressive and lethal forms of lung cancer [1]. It accounts for about 16% of the total lung cancer cases worldwide and is prominently linked to mutagens associated with tobacco smoke [2]. Timely SCLC diagnosis and combinatorial treatment with radiomimetic drugs (such as cisplatin and etoposide) improve the short-term survival rate. Still, acquired resistance to chemotherapeutics with very early relapses is frequently causing treatment failures. SCLC presents additional challenges to the clinician such as frequent paraneoplastic endocrinopathies and metastasis [6]. The average five years survival rate is only 6%
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