RESUMEN
PURPOSE: The overall survival of patients with esophageal squamous cell carcinoma (ESCC) is not high due to the lack of markers to evaluate concurrent chemoradiation therapy (CCRT) resistance. The aim of this study is to use proteomics to identify a protein related to radiation therapy resistance and explore its molecular mechanisms. METHODS AND MATERIALS: Proteomic data for pretreatment biopsy tissues from 18 patients with ESCC who underwent CCRT (complete response [CR] group, n = 8; incomplete response [
RESUMEN
Esophageal cancer is the seventh most common cancer in the world. Although traditional treatment methods such as radiotherapy and chemotherapy have good effects, their side effects and drug resistance remain problematic. The repositioning of drug function provides new ideas for the research and development of anticancer drugs. We previously showed that the Food and Drug Administration-approved drug sulconazole can effectively inhibit the growth of esophageal cancer cells, but its molecular mechanism is not clear. Here, our study demonstrated that sulconazole had a broad spectrum of anticancer effects. It can not only inhibit the proliferation but also inhibit the migration of esophageal cancer cells. Both transcriptomic sequencing and proteomic sequencing showed that sulconazole could promote various types of programmed cell death and inhibit glycolysis and its related pathways. Experimentally, we found that sulconazole induced apoptosis, pyroptosis, necroptosis, and ferroptosis. Mechanistically, sulconazole triggered mitochondrial oxidative stress and inhibited glycolysis. Finally, we showed that low-dose sulconazole can increase radiosensitivity of esophageal cancer cells. Taken together, these new findings provide strong laboratory evidence for the clinical application of sulconazole in esophageal cancer.
Asunto(s)
Neoplasias Esofágicas , Proteómica , Humanos , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Tolerancia a Radiación , Estrés Oxidativo , Apoptosis , GlucólisisRESUMEN
Esophageal cancer is the seventh most common cancer globally. Chemotherapy resistance remains a significant challenge in the treatment of esophageal cancer patients. Cisplatin can damage tumor cells by inducing pyroptosis. However, the underlying molecular mechanisms remain unclear. In this work, we aim to investigate pyroptosis-dependent molecular mechanisms underlying cisplatin sensitivity and find potential biomarkers to predict response to cisplatin-based chemotherapy for esophageal cancer patients. Pyroptosis-associated proteins were screened via proteomics for esophageal cancer (n = 124) and bioinformatics analysis. We observed that high calpain-1 (CAPN1) and calpain-2 (CAPN2) expression were associated with favorable clinical outcomes and prolonged survival in esophageal cancer patients. We employed immunohistochemistry to evaluate the expression of CAPN1 and CAPN2 in pretreatment tumor biopsies from 108 patients with esophageal cancer who received concurrent chemoradiotherapy (CCRT). These results suggested that esophageal cancer patients with high expression of both CAPN1 and CAPN2 are likely to experience a complete response to CCRT and have significantly better survival. Western blotting, LDH release, calpain activity and cell viability assays indicated that cisplatin could activate calpain activity, while calpain inhibition or knockout suppressed cisplatin-induced pyroptosis. Mechanistically, we uncovered a novel mechanism whereby cisplatin induced pyroptosis via activation of a CAPN1/CAPN2-BAK/BAX-caspase-9-caspase-3-GSDME signaling axis in esophageal cancer cells. Collectively, this study is the first to explore the effects of calpain on cisplatin-induced pyroptosis in esophageal cancer cells. Further, our findings also imply that the combination of CAPN1 and CAPN2 could be considered as a promising biomarker of cisplatin sensitivity and prognosis in patients with esophageal cancer, providing a possibility to guide individualized treatment.
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Cisplatino , Neoplasias Esofágicas , Calpaína/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Cisplatino/metabolismo , Cisplatino/farmacología , Cisplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Humanos , Piroptosis , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The clinical efficacy of cisplatin in the treatment of esophageal squamous cell carcinoma (ESCC) is undesirable. Signal transducer and activator of transcription 3ß (STAT3ß), a splice variant of STAT3, restrains STAT3α activity and enhances chemosensitivity in ESCC. However, the underlying molecular mechanisms remain poorly understood. Here, we found that high expression of STAT3ß contributes to cisplatin sensitivity and enhances Gasdermin E (GSDME) dependent pyroptosis in ESCC cells after exposure to cisplatin. Mechanistically, STAT3ß was located into the mitochondria and its high expression disrupts the activity of the electron transport chain, resulting in an increase of ROS in cisplatin treatment cells. While high levels of ROS caused activation of caspase-3 and GSDME, and induced cell pyroptosis. STAT3ß blocked the phosphorylation of STAT3α S727 in mitochondria by interacting with ERK1/2 following cisplatin treatment, disrupting electron transport chain and inducing activation of GSDME. Clinically, high expression of both STAT3ß and GSDME was strongly associated with better overall survival and disease-free survival of ESCC patients. Overall, our study reveals that STAT3ß sensitizes ESCC cells to cisplatin by disrupting mitochondrial electron transport chain and enhancing pyroptosis, which demonstrates the prognostic significance of STAT3ß in ESCC therapy.
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Caspasa 3/genética , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Receptores de Estrógenos/genética , Factor de Transcripción STAT3/genética , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Transporte de Electrón/genética , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Fosforilación/efectos de los fármacos , Piroptosis/efectos de los fármacosRESUMEN
Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes-S1 and S2-based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.