[This corrects the article DOI: 10.1016/j.heliyon.2024.e39861.].

Activated Cdc42-associated kinase 1 (ACK1) is an oncogenic non-receptor kinase that promotes tumor cell survival and impairs T-cell activation. Targeting ACK1 has great promise in cancer control. However, tumor adaptive responses that may limit the anticancer efficacy of ACK1 inhibition (ACK1i) remain unclear. We found that ACK1i treatment triggered the PINK1/PARKIN-mediated adaptive mitophagy by upregulating the mitophagy receptor BNIP3. Mass/Spectrometry and co-immunoprecipitation (Co-IP) results indicated that ACK1 interacted with transcription factor regulatory factor X 2 (RFX2) through its MHR domain, and competitively inhibits RFX2 ubiquitination via the E3 ubiquitin ligase MIB1. Conversely, ACK1i facilitates MIB1-mediated RFX2 ubiquitination and degradation. Moreover, we observed that RFX2 is a transcriptional suppressor of BNIP3 using luciferase reporter gene assays and chromatin immunoprecipitation (ChIP). Overall, ACK1i treatment causes RFX2 instability and thereby diminishes RFX2’s suppressive effects on BNIP3 transcription, leading to BNIP3 accumulation and the activation of mitophagy pathways. This adaptive mitophagy allows NSCLC cells to survive under ACK1 inhibition, potentially reducing the efficacy of ACK1i. ACK1i combined with mitophagy-inhibiting agents may attain a more accomplished response in NSCLC. In conclusion, ACK1i induced mitophagy through the release of RFX2 inhibition on BNIP3 transcription, thereby driving adaptive resistance. Inhibiting mitophagy sensitizes NSCLC to ACK1i.

Programmed cell deaths (PCDs) are crucial for tumor progression. By analyzing 18 PCDs, we generated a robust multigene signature, Combined Cell Death Index (CCDI), comprising necroptosis and autophagy genes for non-small cell lung cancer (NSCLC). The CCDI accurately stratified patients by survival prognosis and predicted immunotherapy responses. We validated CCDI and prioritized CCDI genes using five single-cell RNA sequencing and two spatial transcriptomics datasets. CCDI positively correlates with tumor malignancy, invasiveness, and immunotherapy resistance. Four necroptosis genes (PTGES3, MYO6, CCT6A, and CTSH) may affect cancer cell evolution. In vitro, CTSH overexpression or PTGES3 knockdown inhibited NSCLC cell proliferation and migration while inducing necroptosis with necrosome formation. Moreover, we observed diminished CTSH, heightened PTGES3, and low necroptosis activity in 12 pairs of NSCLC tumors and normal tissues. CTSH overexpression or PTGES3 knockdown induced necroptosis and improved anti-PD1 therapy efficiency in syngeneic cancer mouse models. These findings indicate necroptosis genes as potential therapeutic targets in cancer treatments.

Non-small cell lung cancer (NSCLC) is a primary cause of cancer-related mortality on a global scale. Research increasingly shows that long non-coding RNAs (lncRNAs) play crucial regulatory roles and serve as biomarkers for diagnosis, prognosis, therapy monitoring, and druggable targets in NSCLC. We previously identified HAR1A as a tumor-suppressing lncRNA in NSCLC, with its loss also observed in oral and hepatocellular carcinoma. This study aimed to expand the understanding of the functional role of HAR1A in NSCLC and uncover its underlying mechanisms. Our results demonstrated that elevating HAR1A levels impeded NSCLC cell proliferation and migration but promoted apoptosis, thereby boosting their susceptibility to cisplatin. Subsequently, we discovered that HAR1A enhanced cisplatin's cytotoxicity in NSCLC cells by curbing adaptive autophagy through the downregulation of MYC. Further analysis revealed that HAR1A suppresses MYC by both lowering its transcript levels and promoting protein ubiquitination and degradation, thereby restricting tumor cell proliferation, migration, and adaptive autophagy. In exploring MYC's targets, we observed that MYC upregulated the transcription of heat shock protein 90 alpha family class B member 1 (HSP90AB1/HSP90β) gene. Rescue experiments verified that HAR1A mitigated NSCLC cell proliferation and migration and induced apoptosis through the MYC/HSP90β axis. Finally, we confirmed that HAR1A overexpression increased cisplatin efficacy in nude mouse NSCLC xenograft models.In conclusion, the findings suggest that HAR1A could be a promising therapeutic target in treating NSCLC and biomarkers for predicting chemotherapy outcomes. This study provides new insights into the molecular mechanisms of chemoresistance in NSCLC and underscores the potential of lncRNA-based strategies in cancer therapy.

We previously reported lncRNA HAR1A as a tumor suppressor in non-small cell lung cancer (NSCLC). However, the delicate working mechanisms of this lncRNA remain obscure. Herein, we demonstrated that the ectopic expression of HAR1A inhibited the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of NSCLC cells and enhanced paclitaxel (PTX) sensitivity in vitro and in vivo. We identified the oncogenic protein annexin 2 (ANXA2) as a potential interacting patterner of HAR1A. HAR1A overexpression enhanced ANXA2 ubiquitination and accelerated its degradation via the ubiquitin–proteasome pathway. We further uncovered that HAR1A promoted the interaction between E3 ubiquitin ligase TRIM65 and ANXA2. Moreover, the ANXA2 plasmid transfection could reverse HAR1A overexpression-induced decreases in proliferation, migration, and invasion of NSCLC cells and the activity of the NF-κB signaling pathway. Finally, we found that HAR1A loss in NSCLC might be attributed to the upregulated METTL3. The m6A modification levels of HAR1A were increased in cancer cells, while YTHDF2 was responsible for recognizing m6A modification in the HAR1A, leading to the disintegration of this lncRNA. In conclusion, we found that METTL3-mediated m6A modification decreased HAR1A in NSCLC. HAR1A deficiency, in turn, stimulated tumor growth and metastasis by activating the ANXA2/p65 axis.

Interferon regulatory factor 1 (IRF1) significantly affects tumour occurrence and development. This study aimed to analyse its function as a pan-cancer prognostic indicator. We compared IRF1 expression and prognostic significance in normal and tumour samples from different databases. Accordingly, we performed in vitro experiments and immunohistochemistry (IHC) to investigate the role of IRF1 in non-small cell lung cancer (NSCLC). Our findings indicate that IRF1 expression is significantly correlated with prognosis, the tumour microenvironment, and immune cell infiltration. Furthermore, receiver operating characteristic (ROC) analysis revealed that IRF1 had high accuracy in distinguishing cancerous tissues from normal ones. Notably, IRF1 expression was linked to immune-related and immune checkpoint genes. Cell proliferation, invasion, and migration were significantly related to IRF1 expression. IHC indicated that IRF1 was downregulated in NSCLC tissues. Our study provides comprehensive bioinformatic analysis and experimental verification of IRF1, suggesting its potential as a prognostic biomarker in cancer.

Background Oesophageal squamous cell carcinoma (ESCC) is a lethal malignancy. Immune checkpoint inhibitors (ICIs) showed great clinical benefits for patients with ESCC. We aimed to construct a model predicting prognosis and response to ICIs by integrating diverse programmed cell death (PCD) forms.Methods Genes related to 14 PCDs were collected to generate multi-gene signatures, including apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis. Bulk and single-cell RNA transcriptome datasets were used to develop and validate the model. We assessed the functions of two necroptosis-related genes in ESCC cells by Western blot, co-immunoprecipitation (Co-IP), LDH release assay, CCK-8, and migration assay, followed by immunohistochemistry (IHC) staining on samples of patients with ESCC (n = 67).Findings We built and validated a 16-gene prognostic combined cell death index (CCDI) by combining immunogenic cell death (ICD) and necroptosis signatures. The CCDI could also predict response to ICIs in cancer, as shown by Tumour Immune Dysfunction and Exclusion (TIDE) analysis, confirmed in four independent ICI clinical trials. Trajectory analysis revealed that HOOK1 and CUL4A might affect ESCC cell fate. We found that HOOK1 induced necroptosis and inhibited the proliferation and migration of ESCC cells, while CUL4A exhibited the opposite effects. Co-IP assay confirmed that HOOK1 and CUL4A promoted and reduced necrosome formation in ESCC cells. Data from patients with ESCC further supported that HOOK1 and CUL4A might be a tumour suppressor and oncogene, respectively.Interpretation We constructed a CCDI model with potential in predicting prognosis and response to ICIs in cancer. HOOK1 and CUL4A in the CCDI model are crucial prognostic biomarkers in ESCC. Funding The Natural Science Foundation of China [82172786], The National Cancer Center Climbing Fund of China [NCC201908B06], The Natural Science Foundation of Heilongjiang Province [LH2021H077].Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Here, we describe [Os(eta(6)-bip)(1,3-bib)Cl](2),Cl-2 (bib-Os) (eta(6)-bip=eta(6)-biphenyl,1,3-bib=1,3-di(1H-imidazol-l-y1) benzene), a binuclear Os(II) complex, which was characterized by H-1 NMR and ESI-MS. The results showed that complex bib-Os had good lipophilieiiy (1g P-u/w=1.52) and was easy to accumulate in cells. Complex bib-Os showed high antiproliferative activity against human ovarian A2780 cancer cells (IC50 =4.2 mu mol center dot L-1), producing a large number of reactive oxygen species (ROS) and inducing mitmhondrial morphological damage and membrane potential decline. Lipid peroxide (LPO) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inhibition further verified bib-Os-induced cell death through the ferroptosis pathway.

In this work, we designed a novel bipyridine ruthenium complex Ru-Indole using 3-(2-pyridine-3-vinyl)1H-indoles (Indole) as the ligand with the bipyridine ruthenium precursor Ru(bpy)2Cl2 as the coordination linkage. The structures of ligand and related complexes were characterized by using 1H NMR, ESI-MS and elemental analysis. Using a fluorescence spectrophotometer and an ultraviolet-visible spectrophotometer, it is found that the complex could emit fluorescence under the excitation of UV-Vis light, which realized the visual imaging of the complex in the cell. The introduction of the ligand greatly improved the lipophilicity of the complex Ru-Indole, rendering it to be easier to enter the cell and exhibited better anti tumor activity compared with the ligand Indole and the precursor Ru(bpy)2Cl2. Furthermore, we used flow cytometry, confocal imaging and western blotting to explore the cell death mechanism induced by Ru-Indole. The results show that the complex Ru-Indole could be enriched in the mitochondria and lysosomes of tumor cells, and could change the mitochondrial membrane potential and at last induce the autophagy.

We synthesized two novel mononuclear ruthenium complexes, [Ru(cym)(L)Cl]Cl (Ru-1) and [Ru(bpy)(2)(L)] Cl-2 (Ru-2)(cym=cymene, bpy=2,2'-bipyridine, L=(E)-3-(4-hydroxy-3-methoxyphenyl)-N-((4'-methyl-(2,2'-bipyridin)4-yl)methyl)acrylamide), with the modified natural product trans-ferulic acid. Their structures were determined by H-1 NMR, C-13 NMR and ESI-MS techniques. Optical properties and lipophilicity of complexes were characterized by using the fluorescence and UV-visible spectra. The results suggested that both complexes exhibited high water solubility. Ru-2 showed good fluorescence performance with the maximum emission wavelength at 631 nm in the near infrared area and had pH responsive ability (pH=8 similar to 10). Additionally, Ru-2 exhibited high singlet oxygen quantum yield (Phi=0.70), which might be expected to become an efficient photosensitizer. Both of the complexes binded to CT-DNA through intercalation mode (K-b: 1.210 x 10(4) L.mol(-1) for Ru-1; 1.233 x 10(3) L.mol(-1) for Ru-2) and interacted with BSA with one site, causing static quenching of their fluorescence (K-a: 1.94 x 10(4) for Ru-1; 2.45 x 10(4) for Ru-2).

More than 50% of modern drugs used clinically come from natural products, which cart prevent tumor growth and progression by influencing multiple biological pathways such as blocking cell cycle progression, inhibiting cancer cell survival signaling pathway and regulating immune cells. They also show low toxicity to normal tissues. Metal antitumor drugs represented by cisplatin have been widely-used in clinical practice. However, they also have severe drug resistance and side effects, such as nephrotoxicity and neurotoxicity. Therefore, modified platinum drugs with natural products are beneficial for overcoming their deficiencies. On the other hand, the emergence of arene-metal complexes provides more possibilities for the development of high-efficiency and low-toxicity anticancer drugs due to their good water solubility and low toxicity towards normal organisms. Combining the respective advantages of natural products and metals opened up new opportunities for the development of anti-cancer drugs, and the development of metal complexes based on natural products as anticancer agents has become a research hotspot. In this paper, the research and mechanism of platinum and. arene-metal complexes based on natural products are reviewed comprehensively, and the future development in this field has prospected.

Naproxen ( NPX) was used as precursors to prepare three arene complexes [ Ru (eta(6)-p-cymene) . (NPX-bpy) Cl]Cl( 1) , [Os(eta(6)-p-cymene) ( NPX-bpy) Cl] Cl( 2 ) and [ Ir(eta(5)-Cp* ) ( NPX-bpy ) Cl] Cl( 3 ) with arene ruthenium (Ru) , osmium (Os) and iridium (Ir) dimers. The complexes were characterized by elemental analysis, electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. The cytotoxicity results showed that the three complexes exhibited little cytotoxic activity against the tumor cell lines(IC50>100 mu mol/L) , except that complex 1 has moderate activity on NB-4 cells( IC50 =45. 2 mu mol/L) , which may be attributed to the higher enrichment of complex 1 in the nucleus than complex 2 and 3. In addition, the three complexes could effectively inhibit the expression of COX-2, equivalent to the anti-inflammatory properties of naproxen, and achieved the multi-functional application of anticancer and anti-inflammatory threapy of arene-metal complexes.