Cisplatin-resistant Non-small Cell Lung Cancer Research Articles

Bioorthogonal Chemistry-Guided Inhalable Nanoprodrug to Circumvent Cisplatin Resistance in Orthotopic Nonsmall Cell Lung Cancer.

Pulmonary delivery of anticancer therapeutics has shown encouraging performance in treating nonsmall cell lung cancer (NSCLC), which is characterized by high aggressiveness and poor prognosis. Cisplatin, a key member of the family of DNA alkylating agents, is extensively employed during NSCLC therapy. However, the development of chemoresistance and the occurrence of side effects severely impede the long-term application of cisplatin-based chemotherapies. Herein, we propose a meaningful strategy to precisely treat cisplatin-resistant NSCLC based on the combination of bioorthogonal chemistry with an inhalation approach. Ethacraplatin (EA-Pt), a platinum prodrug (IV), was synthesized and encapsulated in nitric oxide (NO)-containing micelles to overcome cisplatin chemoresistance. By further modifying bioorthogonal molecules in this nanoplatform (EA-Pt@MDBCO), an improved targeting performance toward pulmonary cancerous regions is achieved after prelabeling with azide via inhalation. Upon entering acidic cancer cells, EA-Pt is swiftly released due to the pH sensitivity of bioorthogonal micelles, which enables its bifunctions to inhibit glutathione S-transferase activity and deplete intracellular glutathione, eventually reversing cisplatin resistance. Moreover, the released NO also improves the overall therapeutic outcome against NSCLC. Consequently, inhalable EA-Pt@MDBCO prelabeled by azide effectively inhibits the progression of cisplatin-resistant orthotopic NSCLC, offering a feasible nanostrategy to expand the treatment options for NSCLC.

Co-Delivery of VEGF siRNA and THPP via Metal-Organic Framework Reverses Cisplatin-Resistant Non-Small Cell Lung Cancer and Inhibits Metastasis through a MUC4 Regulating Mechanism.

Cisplatin resistance significantly impacts the antitumor efficacy of cisplatin chemotherapy and contributes to poor prognosis, including metastasis. In this study, we present the utilization of metal-organic framework (MOF) nanoparticles as the therapeutic component and drug loading scaffold for implementing a ternary combination therapeutic strategy to combat cisplatin-resistant lung cancer and metastasis. Specifically, by engineering MOFs (Cis@MOF-siVEGF) through the self-assembly of THPP as photosensitizer for photodynamic therapy (PDT), along with the incorporation of cisplatin (DDP) and VEGF siRNA (siVEGF), we propose the leverage of photodynamic-induced oxidative damage and gene silencing of the angiogenic factor to reverse cisplatin resistance and sensitize therapeutic potency. Our findings demonstrated that the chemo/photodynamic/antiangiogenic triple combination therapy via Cis@MOF-siVEGF under irradiation effectively inhibits cisplatin-resistant tumor growth and induces abscopal effects. Importantly, molecular mechanistic exploration suggested that MUC4 exerted regulatory effects on governing cancer metastasis, thus representing a potential immunotherapeutic target for cancer intervention. Overall, our study creates a MOFs-based multicomponent delivery platform for complementary therapeutic modules with synergistically enhanced antitumor efficacy and sheds light on potential regulatory mechanisms on cisplatin-resistance cancers.

GLIDR-mediated regulation of tumor malignancy and cisplatin resistance in non-small cell lung cancer via the miR-342-5p/PPARGC1A axis

BackgroundLung cancer, particularly non-small cell lung cancer (NSCLC), remains a significant cause of cancer-related mortality, with drug resistance posing a substantial obstacle to effective therapy. LncRNAs have emerged as pivotal regulators of NSCLC progression, suggesting potential targets for cancer diagnosis and treatment. Therefore, identifying new lncRNAs as therapeutic targets and comprehending their underlying regulatory mechanisms are crucial for treating NSCLC.Materials and methodsRNA-sequencing data from 149 lung adenocarcinoma (LUAD) patients, including 130 responders and 19 nonresponders to primary treatment, were analyzed to identify the most effective lncRNAs. The effects and regulatory pathways of the selected lncRNAs on NSCLC and cisplatin resistance were investigated.ResultsGlioblastoma-downregulated RNA (GLIDR) was the most effective lncRNA in nonresponsive NSCLC patients undergoing primary treatment, and it was highly expressed in NSCLC patients and those with cisplatin-resistant NSCLC. Reducing GLIDR expression enhanced cisplatin sensitivity in resistant NSCLC and decreased the malignant characteristics of NSCLC. Moreover, bioinformatic analysis and luciferase assays revealed that microRNA-342-5p (miR-342-5p) directly targets GLIDR. MiR-342-5p overexpression inhibited NSCLC cell proliferation, migration, and invasion, whereas miR-342-5p inhibition promoted NSCLC malignancy, which was rescued by suppressing GLIDR. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PPARGC1A) was identified as a downstream target of miR-342-5p. PPARGC1A inhibition increased cisplatin sensitivity in resistant NSCLC. Moreover, PPARGC1A inhibition suppresses NSCLC malignancy, whereas PPARGC1A overexpression promoted it. Furthermore, GLIDR overexpression was found to counteract the inhibitory effects of miR-342-5p on PPARGC1A, and increased PPARGC1A expression reversed the inhibition of NSCLC malignancies caused by decreased GLIDR.ConclusionsGLIDR is a prognostic marker for cisplatin treatment in NSCLC and a therapeutic target in cisplatin-resistant NSCLC. GLIDR promotes NSCLC progression by sponging miR-342-5p to regulate PPARGC1A expression and regulates cisplatin resistance through the miR-342-5p/PPARGC1A axis, underscoring its potential as a therapeutic target in cisplatin-resistant NSCLC.

Deubiquitinating enzyme USP28 inhibitor AZ1 alone and in combination with cisplatin for the treatment of non-small cell lung cancer

Lung cancer is one of the most common malignant tumors. Despite decades of research, the treatment of lung cancer remains challenging. Non-small cell lung cancer (NSCLC) is the primary type of lung cancer and is a significant focus of research in lung cancer treatment. The deubiquitinase ubiquitin-specific protease 28 (USP28) plays a role in the progression of various tumors and serves as a potential therapeutic target. This study aims to determine the role of USP28 in the progression of NSCLC. We examined the impact of the USP28 inhibitor AZ1 on the cell cycle, apoptosis, DNA damage response, and cellular immunogenicity in non-small cell lung cancer. We observed that AZ1 and siUSP28 induce DNA damage, leading to the activation of Noxa-mediated mitochondrial apoptosis. The dsDNA and mtDNA released from DNA damage and mitochondrial apoptosis activate tumor cell immunogenicity through the cGAS-STING signaling pathway. Simultaneously, targeting USP28 promotes the degradation of c-MYC, resulting in cell cycle arrest and inhibition of DNA repair. This further promotes DNA damage-induced cell apoptosis mediated by the Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA. Moreover, we found that the combination of AZ1 and cisplatin (DDP) can enhance therapeutic efficacy, thereby providing a new strategy to overcome cisplatin resistance in NSCLC. These findings suggest that targeting USP28 and combining it with cisplatin are feasible strategies for treating NSCLC.

Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor

Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Cisplatin, a platinum derivative, has been used as a therapeutic option for treating metastatic NSCLC for several years. However, acquired, or intrinsic drug resistance to Cisplatin is the major obstacle to the successful treatment outcome of patients. Dysregulation of Nrf2 (nuclear factor erythroid 2-related factor 2) and EGFR (epidermal growth factor receptor) signaling have been associated with cellular proliferation, cancer initiation, progression and confer drug resistance to several therapeutic agents including Cisplatin in various cancers. To dissect the molecular mechanism of EGFR activation in resistant cells, we developed Cisplatin-resistant (CisR) human NSCLC cell lines (A549 and NCIH460) with increasing doses of Cisplatin treatment over a 3-month period. CisR cells demonstrated increased proliferative capacity, clonogenic survivability and drug efflux activity compared to the untreated parental (PT) cells. These resistant cells also showed higher levels of Nrf2 and EGFR expression. Here, we found that Nrf2 upregulates both basal and inducible expression of EGFR in these CisR cells at the transcriptional level. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC.

A novel combinatory treatment against a CDDP-resistant non-small cell lung cancer based on a Ruthenium(II)-cyclopentadienyl compound

The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge.Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(η5-C5H4CHO)(Me2bipy)(PPh3)]+ (RT150) and [Ru(η5-C5H4CH2OH)(Me2bipy)(PPh3)][CF3SO3] (RT151) were tested against a panel of cisplatin-resistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against non-transformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential anti-angiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin.To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile.

LncRNA PCIF1 promotes aerobic glycolysis in A549/DDP cells by competitively binding miR-326 to regulate PKM expression

ObjectiveUtilizing transcriptome analysis to investigate the mechanisms and therapeutic approaches for cisplatin resistance in non-small cell lung cancer (NSCLC). MethodsFirstly, the biological characters of A549 cells and A549/DDP cells were detected by RNA sequencing, CCK-8 and hippocampal energy analyzer. Then, the differential Genes were functionally enriched by GO and KEGG and the competitive endogenous RNA network map was constructed. Finally, the effects of the predicted biogenesis pathway on the biological functions of A549/DDP cells were verified by in vitro and in vivo experiments. ResultThe differentially transcribed genes of A549 and A549/DDP cells were analyzed by enrichment analysis and cell biological characteristics detection. The results showed that A549/DDP cells showed significantly increased resistance to cisplatin, glucose metabolism signaling pathway and glycolysis levels compared with A549 cells. Among glycolysis-related transcription genes, PKM had the most significant difference Fold Change is 8. LncRNA PCIF1 is a new marker of A549/DDP cells and can be used as a molecular sponge to regulate the expression of PKM. LncRNA PCIF1 targets miR-326 to induce PKM expression, promote glycolysis level, and enhance the resistance of A549/DDP cells to cisplatin. ConclusionLncRNA PCIF1 as biomarkers of A549/DDP cells, higher expression can induce the PKM, promote cell glycolysis, lead to the occurrence of cisplatin resistance. LncRNA PCIF1 can be considered as a potential target for treating cisplatin-resistant NSCLC.

MiR-3195inhibits non-small cell lung cancer malignant behaviors along with cisplatin resistance through targetingPFKFB4.

Chemotherapy presents the main therapy of non-small cell lung cancer (NSCLC). Nevertheless, cisplatin-based therapy can be limited by drug resistance. MicroRNA (miRNA) possesses a vital regulatory function in modulating the progression as well as cisplatin resistance of NSCLC, but how miR-3195 influences NSCLC is obscure. In this work, it was discovered that miR-3195 presented definite down-regulation in NSCLC cells. Gain-of function assays revealed that overexpressing miR-3195 hindered NSCLC cell proliferation together with migration whereas induced cell apoptosis. Mechanically, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) presented the target gene of miR-3195 and was high-expressed in NSCLC cells. The repressive impacts of overexpressing miR-3195 on NSCLC cells malignant behaviors were reversed via PFKFB4 elevation. Additionally, elevated miR-3195 expression reduced cisplatin resistance of NSCLC both in vitro as well as in vivo. PFKFB4 elevation could offset the reduced cisplatin resistance caused by miR-3195 overexpression in NSCLC cells. In conclusion, this work clarified miR-3195 repressed NSCLC cell proliferation, migration, as well as cisplatin resistance by modulating PFKFB4. Our study might provide a promising clue to promote the anti-tumor effects of chemotherapy.

Sensitive quantification of mevalonate pathway intermediates and prediction of relative novel analogs by chemical derivatization-based LC-MS/MS

The mevalonate (MVA) pathway plays a crucial role in the occurrence and progression of various diseases, such as osteoporosis, breast cancer, and lung cancer, etc. However, determining all the MVA pathway intermediates is still challenging due to their high polarity, low concentration, chelation effect with metal compartments, and poor mass spectrometric response. In this study, we established a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method coupled with N2, N2, N4, N4-tetramethyl-6-(4-(piperazin-1-ylsulfonyl) phenyl)-1,3,5-triazine-2,4-diamine (Tmt-PP) labeling for the simultaneous analysis of all MVA intermediates in biospecimens. Chemical derivatization significantly improved the chromatographic retention, peak shape, and detection sensitivity of the analytes. Moreover, we employed a method named mass spectrum calculation to achieve the absolute quantification of the isomers, i.e., isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). The established method was fully qualified and applied to explore the difference of these metabolites in cisplatin-resistant non-small cell lung cancer (NSCLC) cells. Additionally, several MVA intermediate analogs, including isopentenyl monophosphate or dimethylallyl monophosphate (IMP/DMAMP), geranyl monophosphate (GMP), 5-triphosphomevalonate (MTP), and isopentenyl triphosphate or dimethylallyl triphosphate (ITP/DMATP), were identified for the first time using a knowledge-driven prediction strategy. We further explored the tissue distribution of these novel metabolites. Overall, this work developed a sensitive quantification method for all MVA intermediates, which will enhance our understanding of the role of this pathway in various health and disease conditions. The novel metabolites we discovered warrant further investigations into their biosynthesis and biological functions.

Bithiophene-Functionalized Infrared Two-Photon Absorption Metal Complexes as Single-Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy.

A planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single-molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two-photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA-related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin-resistant non-small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two-photon activatable metal complex may contribute to a new generation of single-molecule-based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

FTO blocks RNA translational activity via the loss of N6-methyladenosine methylation at 5' UTR regulated by RBM5 in cisplatin-resistant NSCLC.

N6-methyladenosine (m6A) methylation has been widely regarded in numerous biological functions including CR. Nonetheless, the molecular process of m6A methylation behind CR in non-small cell lung cancer (NSCLC) has no apparent significance. We identified in this study that the expression of FTO alpha-ketoglutarate dependent dioxygenase (FTO) was downregulated in CR NSCLC tissues and cells in vivo and in vitro. Additionally, RIP-seq indicated that loss of FTO contributed to the elevated m6A methylation at 5'-untranslated region of RNAs which were closely connected with tumor resistance and malignancy, and FTO exerted to exclude the recruitment of eIF3A to these target genes in CR NSCLC. Moreover, FTO-enriched transcripts displayed a reduced translational capability in CR NSCLC compared to the regular NSCLC cells. Finally, we also identified RNA binding motif protein 5 (RBM5) that could specially interact with FTO in regular NSCLC compared to CR NSCLC. Deficiency of RBM5 resulted in the abnormal recognition of transcripts by FTO, and led to the translation silencing of genes associated with CR such as ATP7A, ERCC1, CD99, CDKN3, XRCC5, and NOL3. Taken together, our data characterized FTO as a novel translation regulator and revealed the molecular mechanism on gene translation through the synergistic effects with RBM5 and m6A methylation in CR NSCLC cells.

Evodiamine potentiates cisplatin-induced cell death and overcomes cisplatin resistance in non-small-cell lung cancer by targeting SOX9-β-catenin axis.

In recent decades, phytotherapy has remained as a key therapeutic option for the treatment of various cancers. Evodiamine, an excellent phytocompound from Evodia fructus, exerts anticancer activity in several cancers by modulating drug resistance. However, the role of evodiamine in cisplatin-resistant NSCLC cells is not clear till now. Therefore, we have used evodiamine as a chemosensitizer to overcome cisplatin resistance in NSCLC. Here, we looked into SOX9 expression and how it affects the cisplatin sensitivity of cisplatin-resistant NSCLC cells. MTT and clonogenic assays were performed to check the cell proliferation. AO/EtBr and DAPI staining, ROS measurement assay, transfection, Western blot analysis, RT-PCR, Scratch & invasion, and comet assay were done to check the role of evodiamine in cisplatin-resistant NSCLC cells. SOX9 levels were observed to be higher in cisplatin-resistant A549 (A549CR) and NCI-H522 (NCI-H522CR) compared to parental A549 and NCI-H522. It was found that SOX9 promotes cisplatin resistance by regulating β-catenin. Depletion of SOX9 restores cisplatin sensitivity by decreasing cell proliferation and cell migration and inducing apoptosis in A549CR and NCI-H522CR. After evodiamine treatment, it was revealed that evodiamine increases cisplatin-induced cytotoxicity in A549CR and NCI-H522CR cells through increasing intracellular ROS generation. The combination of both drugs also significantly inhibited cell migration by inhibiting epithelial to mesenchymal transition (EMT). Mechanistic investigation revealed that evodiamine resensitizes cisplatin-resistant cells toward cisplatin by decreasing the expression of SOX9 and β-catenin. The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells

ABSTRACT Non-small cell lung cancer (NSCLC) is among the most difficult malignancies to treat. Type III collagen (COL3A1) can affect the progression and chemoresistance development of NSCLC. We herein explored the mechanism that drives COL3A1 dysregulation in NSCLC. Potential RNA-binding proteins (RBPs) and transcription factors (TFs) that could bind to COL3A1 were searched by bioinformatics. mRNA expression was detected by quantitative PCR. Protein expression was evaluated using immunoblotting and immunohistochemistry. The effects of the variables were assessed by gauging cell growth, invasiveness, migratory capacity, apoptosis, and cisplatin (DDP) sensitivity. The direct YY1/COL3A1 relationship was confirmed by ChIP and luciferase reporter experiments. Xenograft experiments were done to examine COL3A1’s function in DDP efficacy. COL3A1 showed enhanced expression in DDP-resistant NSCLC. In H460/DDP and A549/DDP cells, downregulation of COL3A1 exerted inhibitory functions in cell growth, invasiveness, and migration, as well as promoting effects on cell DDP sensitivity and apoptosis. Mechanistically, ELAV-like RNA binding protein 1 (ELAVL1) enhanced the mRNA stability and expression of COL3A1, and Yin Yang 1 (YY1) promoted the transcription and expression of COL3A1. Furthermore, upregulation of COL3A1 reversed ELAVL1 inhibition- or YY1 deficiency-mediated functions in DDP-resistant NSCLC cells. Additionally, COL3A1 downregulation enhanced the anti-tumor efficacy of DDP in vivo. Our investigation demonstrates that COL3A1 upregulation, induced by both RBP ELAVL1 and TF YY1, exerts important functions in phenotypes of NSCLC cells with DDP resistance, offering an innovative opportunity in the treatment of drug-resistant NSCLC.

XAF1 overexpression inhibits the malignant progression and cisplatin resistance of NSCLC by activating endoplasmic reticulum stress.

XIAP-associated factor 1 (XAF1) has been found to participate in the progression of multiple human cancers. Nevertheless, its role as well as the reaction mechanism in non-small cell lung cancer (NSCLC) still remains obscure. In this study, the protein expression of XAF1 in NSCLC cell lines was evaluated using western blot. With the employment of CCK-8 assay, EdU staining, wound healing and transwell, capabilities of NSCLC cells to proliferate, migrate and invade were assessed. Cell apoptotic level and cell cycle were resolved utilizing flow cytometry. Western blot was applied for the estimation of apoptosis- and endoplasmic reticulum (ER) stress-related proteins. It was discovered that XAF1 expression was conspicuously reduced in NSCLC cell lines. XAF1 overexpression suppressed H1299 cell proliferative, invasive and migrative capabilities, but exhibited promotive effects on cell cycle arrest. Meanwhile, XAF1 overexpression inhibited cisplatin resistance in H1299 and H1299/DDP cells by promoting cell apoptosis and enhanced the expression levels of ER stress-related proteins CHOP, GRP78 and ATF4. What's more, 4-PBA treatment reversed the impacts of XAF1 overexpression on the proliferative, invasive, migrative and apoptotic capabilities of H1299 cells, as well as cell cycle and cisplatin resistance. In conclusion, XAF1 overexpression impeded the advancement of NSCLC and repressed cisplatin resistance of NSCLC cells through inducing ER stress, which indicated that XAF1 might be a novel targeted-therapy for NSCLC.

Meta-analysis of microarray data to determine gene indicators involved in cisplatin resistance in non-small cell lung cancer.

Lung cancer is a major cause of cancer-related mortality worldwide, with a 5-year survival rate of approximately 22%. Cisplatin is one of the standard first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC), but its efficacy is often limited by the development of resistance. Despite extensive research on the molecular mechanisms of chemoresistance, the underlying causes remain elusive and complex. We analyzed three microarray datasets to find the gene signature and key pathways related to cisplatin resistance in NSCLC. We compared the gene expression of sensitive and resistant NSCLC cell lines treated with cisplatin. We found 274 DEGs, including 111 upregulated and 163 downregulated genes, in the resistant group. Gene set enrichment analysis showed the potential roles of several DEGs, such as TUBB2B, MAPK7, TUBAL3, MAP2K5, SMUG1, NTHL1, PARP3, NTRK1, G6PD, PDK1, HEY1, YTHDF2, CD274, and MAGEA1, in cisplatin resistance. Functional analysis revealed the involvement of pathways, such as gap junction, base excision repair, central carbon metabolism, and Notch signaling in the resistant cell lines. We identified several molecular factors that contribute to cisplatin resistance in NSCLC cell lines, involving genes and pathways that regulate gap junction communication, DNA damage repair, ROS balance, EMT induction, and stemness maintenance. These genes and pathways could be targets for future studies to overcome cisplatin resistance in NSCLC.

α-Hederin promotes ferroptosis and reverses cisplatin chemoresistance in non-small cell lung cancer.

Cisplatin is a core chemotherapy regimen in non-small cell lung cancer (NSCLC). However, chemoresistance to cisplatin leads to a poor prognosis in NSCLC. α-Hederin is a natural compound extracted from Nigella sativa. The study aims to explore the effects of α-Hederin on cisplatin resistance in NSCLC. NSCLC cisplatin-resistant cell lines A549/DPP and PC-9 were cultured to evaluate the efficacy of α-Hederin in the treatment of NSCLC in vitro and in vivo. Metabolomics and RNA-seq analysis were used to determine the potential mechanisms of action of α-Hederin. The results showed that α-Hederin inhibited cisplatin-resistant NSCLC cells proliferation and metastasis. Mice xenograft, orthotopic, and metastatic A549/DPP cell models also showed the anti-tumor effects of α-Hederin. The metabolomics and RNA-seq analysis results showed that α-Hederin activated DDIT3/ATF3 pathway and ferroptosis via silencing SLC7A11 and GPX4. Furthermore, α-Hederin enhanced the nuclear expression of EGR1. Bioinformatics and luciferase experiments confirmed that EGR1 binds to the miR-96-5p promoter region, inhibiting transcription. In addition, miR-96-5p directly suppressed the levels of DDIT3. This study revealed that α-Hederin activated EGR1 nuclear translocation and directly repressed miR-96-5p. It also promoted DDIT3/ATF3-mediated ferroptosis and reversed cisplatin resistance in NSCLC.

Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress

Chemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin resistance within NSCLC. Our study revealed enhanced PAK4 expression in both cisplatin-resistant NSCLC tumors and cell lines. Notably, PAK4 silencing led to a remarkable enhancement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin evoked endoplasmic reticulum stress in NSCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GRP78 signaling pathway results in the sensitization of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish PAK4 as a promising therapeutic target for addressing chemoresistance in NSCLC, potentially opening new avenues for enhancing treatment efficacy and patient outcomes.

SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization

The function of SLC7A11 in the process of ferroptosis is well-established, as it regulates the synthesis of glutathione (GSH), thereby influencing tumor development along with drug resistance in non-small cell lung cancer (NSCLC). However, the determinants governing SLC7A11's membrane trafficking and localization remain unknown. Our study identified SPTBN2 as a ferroptosis suppressor, enhancing NSCLC cells resistance to ferroptosis inducers. Mechanistically, SPTBN2, through its CH domain, interacted with SLC7A11 and connected it with the motor protein Arp1, thus facilitating the membrane localization of SLC7A11 — a prerequisite for its role as System Xc−, which mediates cystine uptake and GSH synthesis. Consequently, SPTBN2 suppressed ferroptosis through preserving the functional activity of System Xc− on the membrane. Moreover, Inhibiting SPTBN2 increased the sensitivity of NSCLC cells to cisplatin through ferroptosis induction, both in vitro and in vivo. Using Abrine as a potential SPTBN2 inhibitor, its efficacy in promoting ferroptosis and sensitizing NSCLC cells to cisplatin was validated. Collectively, SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.

Lactate promoted cisplatin resistance in NSCLC by modulating the m6A modification-mediated FOXO3/MAGI1-IT1/miR-664b-3p/IL-6R axis

BackgroundCisplatin resistance is one of the major obstacles in non-small cell lung cancer (NSCLC) treatment. Intriguingly, elevated lactate levels were observed in cisplatin-resistant cells, which spurred further investigation into their underlying biological mechanisms. MethodsLactate levels were measured by lactate detection kit. Cisplatin-resistance NSCLC cells were established using progressive concentration of cisplatin. Cell viability, proliferation, and apoptosis were detected by CCK-8, EdU, and flow cytometry, respectively. Cell proliferation in vivo was determined by immunohistochemistry of Ki67 and apoptotic cells were calculated by the TUNEL. MeRIP-PCR was used to measure FOXO3 m6A levels. The interactions of genes were analyzed via RIP, ChIP, Dual-luciferase reporter, and RNA pull-down, respectively. ResultsElevated lactate levels were observed in both NSCLC patients and cisplatin-resistance cells. Lactate treatment increased cisplatin-resistance cell viability in vitro and promoted tumor growth in vivo. Mechanistically, lactate downregulated FOXO3 by YTHDF2-mediated m6A modification. FOXO3 transcriptionally reduced MAGI1-IT1 expression. FOXO3 overexpression inhibited the lactate-induced promotion of cisplatin resistance in NSCLC, which were reversed by MAGI1-IT1 overexpression. MAGI1-IT1 and IL6R competitively bound miR-664b-3p. FOXO3 overexpression or MAGI1-IT1 knockdown repressed lactate-mediated cisplatin resistance in vivo. ConclusionLactate promoted NSCLC cisplatin resistance through regulating FOXO3/MAGI1-IT1/miR-664b-3p/IL6R axis in YTHDF2-mediated m6A modification.

LncRNA FEZF1-AS1 facilitates cisplatin resistance in non-small cell lung cancer through modulating the miR-32-5p-glutaminase axis.

Non-small cell lung cancer (NSCLC) is one of the prevalent malignancies. Cisplatin (CDDP) is a conventional chemotherapeutic agent against NSCLC. However, inherent and acquired chemoresistance limited the effectiveness of cisplatin in treatment of NSCLC. This study aimed to investigate the roles and underlying mechanisms of lncRNA-FEZF1-AS1 in mediating cisplatin sensitivity in NSCLC. We found that FEZF1-AS1 levels were significantly higher in lung cancer patients and cell lines. Blocking FEZF1-AS1 sensitized lung cancer cells to cisplatin. Additionally, both glutamine metabolism and FEZF1-AS1 were significantly elevated in cisplatin resistant NSCLC cell lines, A549/CDDP R and SK-MES-1 CDDP/R. Analysis using bioinformatics, RNA pull-down assay and luciferase assay demonstrated that FEZF1-AS1 sponged miR-32-5p, which acted as a tumor suppressor in NSCLC. Glutaminase (GLS), a key enzyme in the glutamine metabolism, was predicted and validated as the direct target of miR-32-5p in NSCLC cells. Inhibiting glutamine metabolism or reducing glutamine supply effectively resensitized cisplatin-resistant cells. Furthermore, restoring miR-32-5p in FEZF1-AS1-overexpressing cisplatin resistant cells successfully overcame FEZF1-AS1-mediated cisplatin resistance by targeting GLS. These findings were further supported by in vivo xenograft mice experiments. This study uncovered the roles and molecular mechanisms of lncRNA FEZF1-AS1 in mediating cisplatin resistance in NSCLC, specifically through modulating the miR-32-5p-GLS axis, providing support for the development of new therapeutic approaches against chemoresistant lung cancer.