Sensitivity Of Cells Research Articles

Ovarian cancer is a gynecologic malignancy with high mortality and poor prognosis. Chemoresistance is a key cause of ovarian cancer recurrence and metastasis. It has been found that some bioactive peptides can inhibit the growth and metastasis of cancer cells and promote cell apoptosis, thus exerting anti-cancer effects. Tβ4-17 is a small polypeptide that we selected using ITRAQ technology, and its precursor protein is thymosin β4. This study mainly investigated its effect in combination with cisplatin (DDP) on the proliferation, migration and apoptosis of ovarian cancer resistant cells and related molecular mechanisms. Our results showed that Tβ4-17 peptide combined with DDP significantly inhibited the proliferation and migration of drug resistance cells in ovarian cancer, promoted apoptosis, and increased the chemo-sensitivity of ovarian cancer cells to DDP. In addition, qRT-PCR and Western blot showed that NF-κB was significantly highly expressed in DDP-resistant cells of ovarian cancer. After application of NF-κB inhibitors and activators, Western blot, CCK8, EDU fluorescence proliferation assay, and cell scratch assay showed that Tβ4-17 peptide down-regulated NF-κB p65 protein expression and inhibited cell proliferation and migration. In conclusion, our study demonstrates that Tβ4-17 peptide enhances the sensitivity of ovarian cancer cells to DDP by down-regulating NF-κB expression.

Progesterone resistance is a key factor in the failure of conservative treatment in young endometrial cancer patients, and there is no effective method to predict and reverse progesterone resistance. CTMP is known to be involved in the development and progression of endometrial cancer, but the mechanism is unidentified. In this study, the immunohistochemical method was used to detect the expression of CTMP in the endometrium before and after progesterone treatment. In cell culture experiments, cell growth and proliferation were examined using CCK-8 and EDU incorporation assay. CTMP and PI3K/AKT pathway-related proteins expression were examined using Western blot. The results show that CTMP expression in the progesterone-resistant group of AEH was not significantly different from that in the progestin-sensitive group before treatment. There was no significant change in the expression of CTMP in the AEH progestin-resistant group, whereas there was a significant decrease in the expression of CTMP in the progesterone-sensitive group after treatment. CTMP knockdown enhances the sensitivity of endometrial cancer cells to medroxyprogesterone acetate (MPA) and may act by inhibiting the PI3K/AKT signaling pathway. This study confirms that CTMP may be associated with sensitivity to progestin therapy in endometrial atypical hyperplasia and endometrial cancer. CTMP may induce the development of progesterone resistance in endometrial cancer through activation of the PI3K/AKT signaling pathway.

SET domain-containing 7 (SETD7, also known as KMT7 or SET7/9), a histone lysine methyltransferase (HKMT) responsible for catalyzing histone H3 lysine 4 monomethylation (H3K4me1), has emerged as a key regulator in multiple cancers. However, the biological functions and epigenetic regulatory mechanisms of SETD7 in esophageal squamous cell carcinoma (ESCC) remain unclear. Our study found that SETD7 expression is significantly upregulated in ESCC tissues and positively correlates with clinical staging. Functional analyses revealed that SETD7 promotes ESCC cell proliferation and migration in vitro, while accelerating tumor growth in vivo. Additionally, SETD7 knockdown increased ESCC cell sensitivity to ferroptosis induction, indicating its dual functionality in tumorigenesis and ferroptosis resistance. Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing analysis systematically mapped H3K4me1 modifications in ESCC cells, identifying ALDH1A3 (aldehyde dehydrogenase 1 family member A3) as a key downstream target. Mechanistically, SETD7-mediated H3K4me1 deposition at the ALDH1A3 promoter drives transcriptional activation, increasing the level of reduced coenzyme Q10 (CoQ10H₂) and inhibiting lipid peroxidation. This study reveals a novel epigenetic-metabolic axis (SETD7-H3K4me1-ALDH1A3/NADH/CoQ10H₂) that regulates ESCC progression and ferroptosis sensitivity, which highlights the clinical translational value of SETD7 in ESCC prognosis assessment and therapeutic development. Schematic diagram illustrating the mechanism by which SETD7 accelerates ESCC progression through enhancing ferroptosis resistance. Created with BioRender.

Trans-cinnamaldehyde (TCA), a natural compound isolated from the stem bark of Cinnamon cassia, has been recognized as a potential therapeutic agent for treating various diseases, including inflammatory conditions and diverse cancers. TNF-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis selectively in cancer cells while sparing normal cells. However, resistance to TRAIL-mediated apoptosis is a significant limitation in cancer therapy. This study aimed to investigate whether TCA could enhance the sensitivity of colorectal cancer cells to TRAIL induced apoptosis and to elucidate the underlying molecular mechanisms involved in this synergistic effect. The study was designed to evaluate the antitumor effects of TCA and TRAIL, both individually and in combination, using colorectal cancer cell lines and in vivo models. Various colorectal cancer cell lines and normal cells were treated with TCA, TRAIL, or their combination. Cell viability assays were conducted to determine the synergistic effects. Western blotting was performed to analyze the expression of ER stress-related proteins. Knockdown of DR5 or CHOP was achieved using siRNA to evaluate its role in the combined anticancer effect. in vivo experiments were conducted to confirm the antitumor effects of the TCA and TRAIL combination. We observed that the combination of TCA and TRAIL exhibits synergistic antitumor effects both in vitro and in vivo. The anticancer effect was notably enhanced when TCA and TRAIL were used to treat various colorectal cancer cell lines, but not normal cells. Additionally, the levels of endoplasmic reticulum (ER) stress-related proteins, such as phosphorylated protein kinase RNA-like ER kinase (PERK), phosphorylation of the eukaryotic initiation factor 2 (eIF2α), and C/EBP homologous protein (CHOP), increased in a dose-dependent manner when treated with TCA. Significantly, TCA elevated DR5 expression levels through ER stress. Knockdown of CHOP reduced the combined effect of TCA and TRAIL. TCA enhances TRAIL-induced apoptosis in colorectal cancer cells by inducing ER stress and upregulating DR5 expression. These findings suggest that TCA is a promising agent for overcoming TRAIL resistance and improving its therapeutic efficacy in colorectal cancer treatment.

Background/Objective: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) lacking targeted therapies and characterized by high tumor heterogeneity. In this study, we evaluated the anticancer activity and mechanistic profile of Simalikalactone D (SKD), a quassinoid compound derived from the endemic Puerto Rican tree Simarouba tulae, in three TNBC cell lines, MDA-MB-468, MDA-MB-231, and SUM-149. Methods: MDA-MB-468, MDA-MB-231 and SUM-149 TNBC cells were evaluated for cell viability, proliferation and migration following SKD treatment. Phospho-antibody array, proteomics, and Western blot analyses were used to explore the SKD mechanism of action in MDA-MB-468 and MDA-MB-231 cell lines. Molecular docking was performed to assess SKD’s interaction with potential intracellular targets. Results: SKD exerted a concentration-dependent effect on the three cell lines. However, MDA-MB-468 cells exhibited an IC50 of 67 nM, while the IC50 values for MDA-MB-231 and SUM-149 were 422 nM and 598 nM, respectively. In MDA-MB-468 cells, 100 nM of SKD induced apoptosis, evidenced by the activated caspase-3 activity, PARP-1 cleavage and decrease in Bcl-2 and survivin protein levels. Sublethal SKD (25 nM) impaired migration in MDA-MB-231 cells and reduced proliferation and motility in SUM149 cells. A 6 h SKD treatment markedly reduced phosphorylation of apoptosis-related proteins (p53, BAD, DAXX, AKT1, JUN) and Jak/STAT pathway components, indicating early disruption of intracellular signaling prior to phenotypic changes. Proteomic profiling showed distinct pathway alterations in both MDA-MB-468 and MDA-MB-231 cells, with reduced Integrin β1 (ITGB1) levels emerging as a shared effector. This suggests that SKD broadly disrupts cell adhesion and migration independently of apoptosis-driven cell death. Western blot validation confirmed reduced ITGB1 protein levels across all three TNBC cell lines examined. In silico docking confirmed favorable binding affinities of SKD to both EGFR (ΔG = −6.718 kcal/mol) and STAT4 (ΔG = −8.481 kcal/mol). Conclusions: Overall, our findings suggest that SKD is a potent anticancer agent in a subgroup of TNBC cells.

Stress granule regulator-associated genes predict drug sensitivity, immune infiltration, and prognosis in patients with gastric cancer: Insights from bioinformatic and experimental approaches.

Lactylation is a novel post-translational modification closely related to the glycolytic process, but the regulatory mechanisms between lactylation and glycolysis are far from being elucidated. Lactate dehydrogenase A (LDHA) catalyzes the formation of lactate, which provides the modifying group for protein lactylation. However, whether lactylation occurs on LDHA itself remains unknown. Here, it is found that lactylation promotes the enzymatic activity of LDHA in lung adenocarcinoma (LUAD), which in turn enhances the overall level of cellular lactylation through a positive feedback loop. Screening identified Lys81 and Lys318 as key LDHA lactylation sites, with alanyl-tRNA synthetase 1 (AARS1) serving as the mediating lactyltransferase. Mass spectrometry reveals that numerous proteins involved in DNA nonhomologous end junction (NHEJ), including FEN1, XRCC5, and XRCC6 might be regulated by lactylation. Delactylation of these proteins significantly hinders the formation of FEN1-RAD1-RAD9A-HUS1 complex, thereby leading to dysfunction of NHEJ and increasing the sensitivity of cancer cells to cisplatin. In summary, this work identifies LDHA lactylation as a critical mechanism for accelerating the progression of LUAD and reveals how this lactylation influenced cisplatin sensitivity of LUAD cells, which deepen the understanding of lactylation-mediated tumor progression and provide a potential new anticancer strategy.

Prior research shows that Akt-dependent phosphorylation of TopBP1 in S phase results in the switch of TopBP1/Treslin binding to TopBP1/E2F1 binding, which is important to prevent replication re-initiation in late S and G2 phases. Here, we demonstrate that contact, but not conformational, mutant p53 can override this switch by binding to both TopBP1 and Treslin, thereby facilitating persistent TopBP1/Treslin interaction in late S and G2 phases, which ultimately leads to over-firing of replication initiation. This increases micronuclei formation, which is further enhanced by genotoxic stressors such as doxorubicin, PARP inhibitors, or ATR inhibitors. Consequently, contact mutant p53 increases the sensitivity of cancer cells to a TopBP1-BRCT7/8 inhibitor combined with PARP or ATR inhibitors. Importantly, contact mutant p53 induces micronuclei formation and MRE11 expression, thereby activating cGAS-STING pathway and enhancing response to immune checkpoint inhibition. This finding is validated in murine mammary tumor allografts and further corroborated by clinical data.

HERPUD1 is a protein of the endoplasmic reticulum (ER) that is sensitive to the unfolded protein response (UPR) induced during ER stress and has been linked to ER stress tolerance in cancer cells. Many tumors, including triple-negative breast cancer (TNBC), which lacks an effective treatment, display UPR activity as a malignancy trait. However, whether HERPUD1 provides an ER-dependent mechanistic link for tumorigenic agents and/or potential therapeutic targets remains unknown. To address these possibilities, we first analyzed HERPUD1 expression in breast cancer (BC) biopsies via immunohistochemistry and immunofluorescence, revealing significantly higher levels in BC, including luminal A and TNBC, compared to non-malignant tissue. In TNBC, in addition to epithelial cells, HERPUD1 associated with inflammatory infiltrates, highlighting its potential role in tumor progression. Palmitic acid (PA), a dietary saturated fatty acid, is an obesity-associated tumor risk factor that induces ER stress and activates UPR. Interestingly, MDA-MB-231 cells, but not other BC cell lines, specifically upregulate HERPUD1 together with XBP1s and ATF4, key UPR factors, in response to PA, whereas TG treatment elevated HERPUD1 across all tested cell lines. HERPUD1 silencing reduced TNBC cell proliferation, migration, and invasion while enhancing doxorubicin (DOX) cytotoxicity, in both 2D and 3D cell culture models. HERPUD1 ablation also elevated UPR activation under TG. In contrast, PA-induced stress led to reduced UPR activation and lower IL-6 and IL-8 levels in the absence of HERPUD1 expression. We identified CK2 as a kinase that regulates HERPUD1 stability via Ser-59 phosphorylation. Strikingly, inhibition of CK2 with CX-4945 not only reduced HERPUD1 levels but also increased the sensitivity of BC cells to DOX. HERPUD1-S59D phosphomimetic mutants showed opposite effects.Our findings establish HERPUD1 as a key mediator of PA-driven aggressiveness, dependent on the lipid-handling capacity of TNBC cells and reveals a mechanistic to lipid stress and tumor progression.

The transfer of molecular cargo in exosomes plays a crucial role in cancer progression, influencing metabolic processes, angiogenesis, immune interactions, and invasive capabilities. This review synthesizes current evidence on how exosomes modulate tumor metabolism and drive drug resistance, and outlines therapeutic opportunities. We searched PubMed, Scopus, Web of Science, and Google Scholar for English-language studies using terms related to exosomes/extracellular vesicles, glycolysis, oxidative phosphorylation (OXPHOS), lipid metabolism, and drug resistance/chemoresistance, and integrated the literature qualitatively. Evidence indicates that exosomes reprogram tumor and stromal metabolism by delivering enzymes and non-coding RNAs that boost glycolysis and dampen OXPHOS, activate cancer-associated fibroblasts and extracellular matrix (ECM) remodeling, and modulate ferroptosis. They stimulate angiogenesis (e.g., via vascular endothelial growth factor (VEGF)/Wnt pathways) and promote immune escape through programmed death-ligand 1 (PD-L1), transforming growth factor beta (TGF-β), and macrophage reprogramming. Exosomal integrins and proteases contribute to epithelial-mesenchymal transition (EMT), organotropism, and pre-metastatic niche formation. Critically, exosomes propagate chemoresistance by exporting drugs and spreading determinants-including P-gp/BCRP/MRP-1, anti-apoptotic proteins, and regulatory RNAs-to previously sensitive cells; adipose-derived vesicles and lipid cargos further reinforce metabolic plasticity and therapy resistance. Given their stability, nanoscale dimensions, and ability to cross the blood-brain barrier, exosomes are promising vectors for targeted delivery; engineered vesicles can enhance chemotherapy responsiveness and counteract resistance, particularly alongside immunotherapy. In summary, interventions that disrupt exosome biogenesis, cargo loading, or uptake-paired with engineered exosomes for precision delivery-could mitigate drug resistance, metastasis, and immune evasion and advance more effective cancer treatment.

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is a molecularly and pathogenically heterogenous disease with varying clinical outcomes, as reflected by the significant number of patients who develop relapse/refractory disease (rrDLBCL) following standard treatment with the combined R-CHOP regimen. The molecular background of rrDLBCL is not yet fully understood, and prognostic and/or companion diagnostic biomarkers for identification and treatment stratification of these patients are in high demand. Methods: This exploratory study used comprehensive proteomic data to identify proteins associated with treatment response. Proteome profiles of DLBCL cells were analyzed through groupwise comparison between cell lines with a resistant or sensitive response to rituximab, cyclophosphamide, doxorubicin, and vincristine. Their responses were determined using subsequent drug response screens, mimicking the conditions of diagnostic samples prior to treatment. Results: A total of 98 differentially abundant proteins, including NSFL1C, GET4, PCNA, and SMC5, were found between resistant and sensitive cells. These same 98 proteins were examined in two cohorts of DLBCL patients, leading to the identification of 16 proteins whose expression was consistently associated with treatment response both in vitro and in patient tissue samples. Among these, GET4 and NSFL1C showed the highest enrichment in R-CHOP resistant patients compared to sensitive responders. In the cell line study, GET4 was enriched in cyclophosphamide-resistant cell lines and NSFL1C enriched in vincristine-resistant cell lines, associating GET4 and NSFL1C enrichment in patient samples to responsiveness to cyclophosphamide and vincristine, respectively. Enrichment of DNA damage repair proteins was observed within the differential proteins, highlighting the need to investigate DNA damage repair involvement in treatment responses. Conclusions: This study identifies 16 proteins with concordant treatment response specificity in DLBCL cell lines and lymphoma tissue patient samples, suggesting their potential as prognostic markers for DLBCL.

The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.

Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lenvatinib is a common first-line treatment for advanced HCC. However, resistance to lenvatinib is the greatest challenge limiting its clinical application. Currently, the molecular mechanisms of resistance remain poorly understood. Methods The expression of DDX1 and Ephrin-A3 in lenvatinib-resistant HCC cells was identified via RNA-seq and Western blotting. Bioinformatic analyses were applied to explore its expression and prognostic role. The biological role of DDX1 was evaluated via CCK8, EdU, flow cytometry analyses and xenograft tumor model. The regulation between DDX1 and Ephrin-A3 was determined by mass spectrometry, coimmunoprecipitation, RNA Immunoprecipitation, and RNA stability assay. Results We successfully established lenvatinib-resistant HCC cells. Theresults of RNA-seq showed DDX1 and Ephrin-A3 were significantly increased in lenvatinib-resistant HCC cells compared to parental cell. The DDX1 expression in HCC tissues is positively associated with worse prognosis. DDX1 knockdown increased the sensitivity of cells to lenvatinib by inhibiting proliferation and promoting apoptosis in vitro and in vivo. Conversely, overexpression of DDX1 exhibited the opposite regulation. Moreover, DDX1 bound to Ephrin-A3 and regulated its expression levels. The effects of DDX1 overexpression on cell proliferation, apoptosis, and lenvatinib resistance were significantly blocked by Ephrin-A3 knockdown. Mechanistically, DDX1 promotes lenvatinib resistance in HCC by regulating Ephrin-A3 mRNA stability and activating the Wnt/β-catenin pathway.Conclusion: The increased DDX1 expression in HCC cells promotes lenvatinib resistance via regulating Ephrin-A3 mRNA stability and activating the Wnt/β-catenin pathway, indicating that targeting DDX1 may be an important strategy for overcoming lenvatinib resistance.

Glucocorticoids are essential for fetal organ maturation and form the basis of antenatal corticosteroid therapy that has significantly reduced preterm-related morbidity such as respiratory distress syndrome (RDS). However, neonatal morbidity remains a clinical challenge regardless of antenatal corticosteroid therapy. Currently, it is thought that adverse intrauterine environments dysregulate glucocorticoid receptor (GR) homeostasis, yet the biological mechanisms remain poorly understood. Therefore, we aimed to study ex vivo glucocorticoid sensitivity in cord blood immune cells from two independent preterm cohorts to identify associations with neonatal morbidity and uncover potential mechanisms of dysregulated glucocorticoid homeostasis. In the first cohort, thawed cord blood mononuclear cells were exposed to betamethasone in the presence of lipopolysaccharides (LPS) for 4 h. In the second cohort, freshly isolated white blood cells were treated with dexamethasone under unstimulated and LPS-stimulated conditions for 48 h. GR isoform expression and regulation of transactivated and transrepressed genes were assessed via qPCR, immunoblotting, flow cytometry, and ELISA. In both cohorts, reduced GR expression, particularly of the GRα isoform, was observed in neonates with morbidity, but only with culture time and not in freshly isolated cells. Ex vivo impaired glucocorticoid-mediated transrepression of proinflammatory genes IL6 and TNF was also observed in the morbidity groups. In contrast, all samples were comparable in basal immune cell distributions and transactivation of glucocorticoid response element (GRE)-dependent genes GILZ and FKBP5, irrespective of neonatal morbidity. These findings suggest that neonates that develop morbidities experience an early postnatal GR dysfunction that is potentially programmed in utero. Moreover, under conditions of decreased GR abundance, classical transactivation functions appear to be preserved at the expense of more complex regulatory mechanisms such as transrepression.

Osimertinib is widely used to treat non-small-cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations. However, osimertinib resistance inevitably develops in almost all patients. In our study, osimertinib-resistant HCC827/OR and PC-9/OR cells were established from parental osimertinib-sensitive cells, and osimertinib (AZD9291) and NHWD870, a bromodomain and extra-terminal (BET) inhibitor, were used to treat cells and mice. PC-9/OR and HCC827/OR cells were subcutaneously injected into mice to establish a mouse model of NSCLC. Luciferase, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) assays were applied to analyze transcription factors (TFs) binding to the APT1 promoter. MST1 palmitoylation was examined with acyl resin-assisted capture (Acyl-RAC) assays. The interaction of YAP1 and BRD4 was evaluated by co-immunoprecipitation (Co-IP) and GST-pull down assays. Our study showed that YAP1 was highly expressed, and its nuclear translocation was increased in osimertinib-resistant NSCLC cells, and silencing of YAP1 overcame osimertinib resistance. BRD4 was upregulated, and NHWD870 significantly reversed YAP1-mediated osimertinib resistance. Moreover, decreased MST1 palmitoylation at C699 was observed in NSCLC cells that are resistant to osimertinib. Furthermore, knockdown of APT1 reduced YAP1 nuclear translocation and APT1-mediated MST1 depalmitoylation restored osimertinib sensitivity. Inhibition of BRD4 blocked YAP1-mediated APT1 transcription in NSCLC cells. In addition, the BRD4 inhibitor disrupted MST1 depalmitoylation by APT1 and recovered osimertinib sensitivity. In vivo administration of NHWD870 enhanced NSCLC cell sensitivity to osimertinib. These findings indicate that inhibition of BRD4 enhances NSCLC cell sensitivity to osimertinib through the APT1-MST1-YAP1 axis.Inhibition of BRD4 sensitized non–small-cell lung cancer (NSCLC) cells to osimertinib by blocking YAP1-mediated APT1 transcription and disrupting APT1-mediated depalmitoyation of MST1 and YAP1 nuclear translocation, which restores osimertinib sensitivity through the APT1-MST1-YAP1 axis in NSCLC. Our study provides a novel mechanism of osimertinib resistance and suggests potential therapeutic strategies for NSCLC.

The cover image is based on the article Glutaminase‐1 Mediated Glutaminolysis to Glutathione Synthesis Maintains Redox Homeostasis and Modulates Ferroptosis Sensitivity in Cancer Cells by Changsen Bai et al., https://doi.org/10.1111/cpr.70036 . image

Deficiency of aldehyde dehydrogenase 2 sensitizes cells to glutamate-induced cytotoxicity via elevation of GluN1 expression.

Pentagalloyl glucose reverses chemoresistance in triple-negative breast cancer via EMT inhibition and miRNA modulation.

GLI2/Parkin-mediated mitophagy promotes pazopanib resistance in clear cell renal cell carcinoma.

YY1-glycolytic axis promotes high glucose-induced cancer stemness in endometrial cancer: A multi-omics guided therapeutic strategy.