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CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.

ABSTRACT: Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in patients with non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca²⁺ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation and, in turn, enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca²⁺-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.

SUBMITTER: Jin Z

PROVIDER: S-EPMC10460435 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.

Jin Zihui Z Zhao Lingling L Chang Yixin Y Jin Rongjia R Hu Fangyu F Wu Shuang S Xue Zixuan Z Ma Yimeng Y Chen Chenglin C Zheng Minghui M Chang Yuanyuan Y Jin Honglei H Xie Qipeng Q Huang Chuanshu C Huang Haishan H

Cell death & disease 20230826 8

Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in patients with non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In ...[more]

PMID: 37633993

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Project description:BackgroundThe benefits of first-line, cisplatin-based chemotherapy for muscle-invasive bladder cancer are limited due to intrinsic or acquired resistance to cisplatin. Increasing evidence has revealed the implication of cancer stem cells in the development of chemoresistance. However, the underlying molecular mechanisms remain to be elucidated. This study investigates the role of LASS2, a ceramide synthase, in regulating Wnt/β-catenin signaling in a subset of stem-like bladder cancer cells and explores strategies to sensitize bladder cancer to cisplatin treatment.MethodsData from cohorts of our center and published datasets were used to evaluate the clinical characteristics of LASS2. Flow cytometry was used to sort and analyze bladder cancer stem cells (BCSCs). Tumor sphere formation, soft agar colony formation assay, EdU assay, apoptosis analysis, cell viability, and cisplatin sensitivity assay were used to investigate the functional roles of LASS2. Immunofluorescence, immunoblotting, coimmunoprecipitation, LC-MS, PCR array, luciferase reporter assays, pathway reporter array, chromatin immunoprecipitation, gain-of-function, and loss-of-function approaches were used to investigate the underlying mechanisms. Cell- and patient-derived xenograft models were used to investigate the effect of LASS2 overexpression and a combination of XAV939 on cisplatin sensitization and tumor growth.ResultsPatients with low expression of LASS2 have a poorer response to cisplatin-based chemotherapy. Loss of LASS2 confers a stem-like phenotype and contributes to cisplatin resistance. Overexpression of LASS2 results in inhibition of self-renewal ability of BCSCs and increased their sensitivity to cisplatin. Mechanistically, LASS2 inhibits PP2A activity and dissociates PP2A from β-catenin, preventing the dephosphorylation of β-catenin and leading to the accumulation of cytosolic phospho-β-catenin, which decreases the transcription of the downstream genes ABCC2 and CD44 in BCSCs. Overexpression of LASS2 combined with a tankyrase inhibitor (XAV939) synergistically inhibits tumor growth and restores cisplatin sensitivity.ConclusionsTargeting the LASS2 and β-catenin pathways may be an effective strategy to overcome cisplatin resistance and inhibit tumor growth in bladder cancer patients.

Project description:BackgroundNon-small cell lung cancer (NSCLC), the most prevalent lung cancer subtype, presents significant treatment challenges. Cisplatin (CP)-based regimens are central to the treatment of multiple solid tumors, but its use is restricted due to its dose-related renal toxicity. We previously found that fluorofenidone {1-[3-fluorophenyl]-5-methyl-2-[(1H)]-pyridone (AKF-PD)} effectively reverses CP-induced acute kidney injury (AKI). However, it remains unclear whether AKF-PD can synergistically ameliorate NSCLC when used together with CP. Thus, this study sought to investigate the effect of AKF-PD on NSCLC and examined its combinatory use with CP for cancer treatment.MethodsWe conducted cell viability assays, 5-ethynyl-2'-deoxyuridine (EdU) experiments, colony-forming assays, wound-healing tests, and Transwell experiments in A549 and H1299 cells to explore the effects of AKF-PD on NSCLC. We then detected the epithelial-mesenchymal transition (EMT) markers [i.e., epithelial cadherin (E-cadherin), matrix metallopeptidase 9 (MMP9), vimentin, and snail family transcriptional repressor 1 (SNAIL)], phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK), to identify the potential mechanisms of AKF-PD. Further, via the combined use of AKF-PD and CP, we found that AKF-PD enhanced the antitumor effect of CP, and we suggest that this may be due to its inhibitory effect on EMT. We also examined the effect of combining AKF-PD and CP in other cancer cell lines, including Hela, SiHA, MDA-MB-231, 5-8F, and UM-UC-3 cells.ResultsAKF-PD significantly inhibited the proliferation and invasion of NSCLC cells (A549 and H1299), suppressed the activation of the MAPK and PI3K/AKT/mTOR pathways, and inhibited the EMT of the tumor cells. When AKF-PD was used in combination with CP, these effects were further enhanced. We also found that AKF-PD enhanced the anti-cancer effect of CP in a variety of cancer cell lines, including cervical cancer (Hela cells and SiHA cells), nasopharyngeal cancer (5-8F cells), triple-negative breast cancer (MDA-MB-231 cells), and bladder cancer (UM-UC-3 cells).ConclusionsAKF-PD not only mitigates CP-induced AKI but also enhances the anti-cancer efficacy of CP. Our findings provide valuable insights into the treatment of NSCLC and may have clinical applications.

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CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.

Publications

CRTAC1 enhances the chemosensitivity of non-small cell lung cancer to cisplatin by eliciting RyR-mediated calcium release and inhibiting Akt1 expression.

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