Low-dose Diosbulbin-B (DB) activates tumor-intrinsic PD-L1/NLRP3 signaling pathway mediated pyroptotic cell death to increase cisplatin-sensitivity in gastric cancer (GC)

Abstract Background Emerging evidences suggests that Diosbulbin-B (DB) is effective to improve cisplatin (DDP)-sensitivity in gastric cancer (GC), but its molecular mechanisms were not fully delineated, and this study managed to investigate this issue. Methods Genes expressions were determined by Real-Time qPCR and Western Blot at transcriptional and translational levels. Cell proliferation and viability were evaluated by cell counting kit-8 (CCK-8) and trypan blue staining assay. Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The Spheroid formation assay was used to evaluated cell stemness. The xenograft tumor-bearing mice models were established, and the tumors were monitored and the immunohistochemistry (IHC) was employed to examine the expressions and localization of Ki67 protein in mice tumor tissues. Results Low-dose DB (12.5 μM) downregulated PD-L1 to activate NLRP3-mediated pyroptosis, and inhibited cancer stem cells (CSCs) properties, to sensitize cisplatin-resistant GC (CR-GC) cells to cisplatin. Mechanistically, the CR-GC cells were obtained, and either low-dose DB or cisplatin alone had little effects on cell viability in CR-GC cells, while low-dose DB significantly induced apoptotic cell death in cisplatin treated CR-GC cells. In addition, low-dose DB triggered cell pyroptosis in CR-GC cells co-treated with cisplatin, which were abrogated by silencing NLRP3. Next, CSCs tended to be enriched in CR-GC cells, instead of their parental cisplatin-sensitive GC (CS-GC) cells, and low-dose DB inhibited spheroid formation and stemness biomarkers (SOX2, OCT4 and Nanog) expressions to eliminate CSCs in CR-GC cells, which were reversed by upregulating programmed death ligand-1 (PD-L1). Furthermore, we proved that PD-L1 negatively regulated NLRP3 in CR-GC cells, and low-dose DB activated NLRP3-mediated pyroptotic cell death in cisplatin treated CR-GC cells by downregulating PD-L1. Also, low-dose DB aggravated the inhibiting effects of cisplatin on tumorigenesis of CR-GC cells in vivo. Conclusions Collectively, low-dose DB regulated intrinsic PD-L1/NLRP3 pathway to improve cisplatin-sensitivity in CR-GC cells, and this study provided alternative therapy treatments for GC.

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Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

10.21203/rs.3.rs-56315/v1 ◽

2020 ◽

Author(s):

Chunfeng Li ◽

Junqiang Qiu ◽

Yingwei Xue

Keyword(s):

Gastric Cancer ◽

Cell Death ◽

Cell Viability ◽

Low Dose ◽

Apoptotic Cell ◽

Cell Counting ◽

Blue Staining ◽

Spheroid Formation ◽

Cisplatin Sensitivity

Abstract Background: Generation of cisplatin (DDP)-resistance by gastric cancer (GC) cells seriously limits the therapeutic efficacy of this drug in clinic, and recent data suggested that Diosbulbin-B (DB), the main anti-tumor compound of Dioscorea bulbifera L, was effective to improve cisplatin-sensitivity in GC cells. However, the underlying mechanisms are still largely unknown.Methods: Genes expressions were determined by Real-Time qPCR and Western Blot. Cell viability was evaluated by cell counting kit-8 and trypan blue staining assay. Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The Spheroid formation assay was used to evaluated cell stemness. Immunohistochemistry (IHC) was employed to examine the expressions and localization of Ki67 protein in mice tumor tissues.Results: Here we found that low-dose DB (12.5 μM) downregulated PD-L1 to activate NLRP3-medicated pyroptosis, and inhibited cancer stem cells (CSCs) properties, to sensitize cisplatin-resistant GC (CR-GC) cells to cisplatin. Mechanistically, the CR-GC cells were obtained, and either low-dose DB or cisplatin alone had little effects on cell viability in CR-GC cells, while low-dose DB significantly induced apoptotic cell death in cisplatin treated CR-GC cells. In addition, low-dose DB triggered cell pyroptosis in CR-GC cells stimulated with cisplatin, which were abrogated by silencing NLRP3. Next, CSCs tended to be enriched in CR-GC cells, instead of their parental cisplatin-sensitive GC (CS-GC) cells, and low-dose DB (12.5 μM) inhibited spheroid formation and stemness biomarkers (CD44, CD133, SOX2, OCT4 and Nanog) expressions to eliminate CSCs in CR-GC cells, which were reversed by upregulating programmed death ligand-1 (PD-L1). Furthermore, we proved that PD-L1 negatively regulated NLRP3 in CR-GC cells, and low-dose DB (12.5 μM) activated NLRP3-mediated pyroptotic cell death in cisplatin treated CR-GC cells by downregulating PD-L1. Also, low-dose DB aggravated the inhibiting effects of cisplatin on tumorigenesis of CR-GC cells in vivo. Conclusions: Collectively, low-dose DB (12.5 μM) regulated intrinsic PD-L1/NLRP3 pathway to improve cisplatin-sensitivity in CR-GC cells, and this study provided alternative therapy treatments for GC.

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Overexpressed LncRNA ADAMTS9-AS2 inhibited gastric cancer (GC) development and sensitized chemoresistant GC cells to cisplatin by regulating miR-223-3p/NLRP3 axis

10.21203/rs.2.22861/v1 ◽

2020 ◽

Author(s):

Niansheng Ren ◽

Tao Jiang ◽

Chengbo Wang ◽

Shilin Xie ◽

Yanwei Xing ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Death ◽

Cell Viability ◽

Pearson Correlation ◽

Luciferase Reporter ◽

Blue Staining ◽

Luciferase Reporter Gene ◽

Kaplan Meier ◽

Cisplatin Sensitivity ◽

Cancer Tissues

Abstract Background The role of LncRNA ADAMTS9-AS2 in the regulation of pathogenesis and chemoresistance of gastric cancer (GC) is largely unkonwn, and this study aimed to solve this problem. Methods Real-Time qPCR was used to examine LncRNA ADAMTS9-AS2 and miR-223-3p expressions, and pearson correlation analysis was conducted to analyse their correlations. Kaplan-Meier survival analysis was performed to evaluate prognosis of GC patients. Dual-luciferase reporter gene system and pull-down assay were employed to validate the target sites of LncRNA ADAMTS9-AS2, miR-223-3p and NLRP3 mRNA. Cell viability was evaluated by CCK-8 assay, trypan blue staining and colony formation assay. Cell apoptosis ratio was detected by FCM and TUNEL assay. Transwell assay for cell migration and Western Blot for protein expressions. ELISA was used to measure cytokines secretion. FISH was conducted to examine LncRNA ADAMTS9-AS2 expressions and localization in mice cancer tissues. Results LncRNA ADAMTS9-AS2 was low-expressed in GC tissues and cells compared to their normal counterparts. Besides, LncRNA ADAMTS9-AS2 inhibited miR-223-3p expressions in GC cells by acting as competing endogenous RNA, and the levels of LncRNA ADAMTS9-AS2 and miR-223-3p showed negative correlations in GC tissues. Of note, overexpression of LncRNA ADAMTS9-AS2 inhibited GC cell viability and motility by sponging miR-223-3p. In addition, the levels of LncRNA ADAMTS9-AS2 were lower, and miR-223-3p was higher in cisplatin-resistant GC (CR-GC) cells than their parental cisplatin-sensitive GC (CS-GC) cells. LncRNA ADAMTS9-AS2 overexpression enhanced the cytotoxic effects of cisplatin on CR-GC cells, which were reversed by overexpressing miR-223-3p. Furthermore, LncRNA ADAMTS9-AS2 increased NLRP3 expressions by targeting miR-223-3p, and upregulation of LncRNA ADAMTS9-AS2 triggered pyroptotic cell death in cisplatin treated CR-GC cells by activating NLRP3 inflammasome through downregulating miR-223-3p. Finally, the promoting effects of LncRNA ADAMTS9-AS2 overexpression on CR-GC cell death were abrogated by pyroptosis inhibitor NSA.Conclusions LncRNA ADAMTS9-AS2 acted as a tumor suppressor and enhanced cisplatin sensitivity in GC cells by regulating miR-223-3p/NLRP3 axis mediated pyroptosis.

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Iron toxicity, lipid peroxidation and ferroptosis after intracerebral haemorrhage

Stroke and Vascular Neurology ◽

10.1136/svn-2018-000205 ◽

2019 ◽

Vol 4 (2) ◽

pp. 93-95 ◽

Cited By ~ 17

Author(s):

Jieru Wan ◽

Honglei Ren ◽

Jian Wang

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Intracerebral Haemorrhage ◽

Neuronal Death ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Iron Toxicity ◽

Secondary Brain Injury

Intracerebral haemorrhage (ICH) is a devastating type of stroke with high mortality and morbidity. However, we have few options for ICH therapy and limited knowledge about post-ICH neuronal death and related mechanisms. In the aftermath of ICH, iron overload within the perihaematomal region can induce lethal reactive oxygen species (ROS) production and lipid peroxidation, which contribute to secondary brain injury. Indeed, iron chelation therapy has shown efficacy in preclinical ICH studies. Recently, an iron-dependent form of non-apoptotic cell death known as ferroptosis was identified. It is characterised by an accumulation of iron-induced lipid ROS, which leads to intracellular oxidative stress. The ROS cause damage to nucleic acids, proteins and lipid membranes, and eventually cell death. Recently, we and others discovered that ferroptosis does occur after haemorrhagic stroke in vitro and in vivo and contributes to neuronal death. Inhibition of ferroptosis is beneficial in several in vivo and in vitro ICH conditions. This minireview summarises current research on iron toxicity, lipid peroxidation and ferroptosis in the pathomechanisms of ICH, the underlying molecular mechanisms of ferroptosis and the potential for combined therapeutic strategies. Understanding the role of ferroptosis after ICH will provide a vital foundation for cell death-based ICH treatment and prevention.

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Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice

Human Molecular Genetics ◽

10.1093/hmg/ddaa062 ◽

2020 ◽

Vol 29 (10) ◽

pp. 1624-1634

Author(s):

Huijuan Xu ◽

Chao Qu ◽

Li Gan ◽

Kuanxiang Sun ◽

Junkai Tan ◽

...

Keyword(s):

Cell Death ◽

Er Stress ◽

Molecular Mechanisms ◽

Histopathological Examination ◽

Apoptotic Cell ◽

Macular Dystrophy ◽

Cone Cell ◽

Rod Cells ◽

Cone Cells

Abstract Variants in interphotoreceptor matrix proteoglycans (IMPG2) have been reported in retinitis pigmentosa (RP) and vitelliform macular dystrophy (VMD) patients. However, the underlying molecular mechanisms remain elusive due to a lack of suitable disease models. We developed two independent Impg2 knockout (KO) mouse models using the CRISPR/Cas9 technique to assess the in vivo functions of Impg2 in the retina. Impg2 ablation in mice recapitulated the RP phenotypes of patients, including an attenuated electroretinogram (ERG) response and the progressive degeneration of photoreceptors. The histopathological examination of Impg2-KO mice revealed irregularly arranged rod cells and mislocalized rhodopsin protein in the inner segment at 6 months of age. In addition to the pathological changes in rod cells, cone cells were also affected in KO retinas. KO retinas exhibited progressive cone cell death and impaired cone cell elongation. Further immunoblotting analysis revealed increased levels of endoplasmic reticulum (ER) stress-related proteins, including C/EBP homologous protein (CHOP), immunoglobulin heavy-chain-binding protein (BIP) and protein disulfide isomerase (PDI), in Impg2-KO mouse retinas. Increased gliosis and apoptotic cell death were also observed in the KO retinas. As autophagy is closely associated with ER stress, we then checked whether autophagy was disturbed in Impg2-KO mouse retinas. The results showed that autophagy was impaired in KO retinas, as revealed by the increased accumulation of SQSTM1 and other proteins involved in autophagy. Our results demonstrate the essential roles of Impg2 in the retina, and this study provides novel models for mechanistic investigations and development of therapies for RP caused by IMPG2 mutations.

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Cell Death and Ageing – A Question of Cell Type

The Scientific World JOURNAL ◽

10.1100/tsw.2002.163 ◽

2002 ◽

Vol 2 ◽

pp. 943-948 ◽

Cited By ~ 2

Author(s):

Pidder Jansen-Dürr

Keyword(s):

Cell Death ◽

Molecular Mechanisms ◽

Replicative Senescence ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Ageing Process ◽

Human Ageing

Replicative senescence of human cells in primary culture is a widely accepted model for studying the molecular mechanisms of human ageing. The standard model used for studying human ageing consists of fibroblasts explanted from the skin and grown intoin vitrosenescence. From this model, we have learned much about molecular mechanisms underlying the human ageing process; however, the model presents clear limitations. In particular, a long-standing dogma holds that replicative senescence involves resistance to apoptosis, a belief that has led to considerable confusion concerning the role of apoptosis during human ageing. While there are data suggesting that apoptotic cell death plays a key role for ageingin vitroand in the pathogenesis of various age-associated diseases, this is not reflected in the current literature onin vitrosenescence. In this article, I summarize key findings concerning the relationship between apoptosis and ageingin vivoand also review the literature concerning the role of apoptosis during in vitro senescence. Recent experimental findings, summarized in this article, suggest that apoptotic cell death (and probably other forms of cell death) are important features of the ageing process that can also be recapitulated in tissue culture systems to some extent. Another important lesson to learn from these studies is that mechanisms ofin vivosenescence differ considerably between various histotypes.

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All-trans-retinoic acid-mediated cytoprotection in LLC-PK1 renal epithelial cells is coupled to p-ERK activation in a ROS-independent manner

AJP Renal Physiology ◽

10.1152/ajprenal.00085.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. F1200-F1208 ◽

Cited By ~ 4

Author(s):

Jessica M. Sapiro ◽

Terrence J. Monks ◽

Serrine S. Lau

Keyword(s):

Cell Death ◽

Retinoic Acid ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Independent Manner ◽

Toxicant Exposure ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Survival Pathways

Although all- trans-retinoic acid (ATRA) provides protection against a variety of conditions in vivo, particularly ischemia, the molecular mechanisms underpinning these effects remain unclear. The present studies were designed to assess potential mechanisms by which ATRA affords cytoprotection against renal toxicants in LLC-PK1 cells. Pretreatment of LLC-PK1 cells with ATRA (25 μM) for 24 h afforded cytoprotection against oncotic cell death induced by p-aminophenol (PAP), 2-(glutathion- S-yl)hydroquinone (MGHQ), and iodoacetamide but not against apoptotic cell death induced by cisplatin. Inhibition of protein synthesis with cycloheximide blunted ATRA protection, indicating essential cell survival pathways must be engaged before toxicant exposure to provide cytoprotection. Interestingly, ATRA did not prevent the PAP-induced generation of reactive oxygen species (ROS) nor did it alter glutathione levels. Moreover, ATRA had no significant effect on Nrf2 protein expression, and the Nrf2 inducers sulforaphane and MG132 did not influence ATRA cytoprotection, suggesting cytoprotective pathways beyond those that influence ROS levels contribute to ATRA protection. In contrast, ATRA rapidly (15 min) induced levels of the cellular stress kinases p-ERK and p-AKT at concentrations of ATRA (10 and 25 μM) required for cytoprotection. Consistent with a role for p-ERK in ATRA-mediated cytoprotection, inhibition of p-ERK with PD98059 reduced the ability of ATRA to afford protection against PAP toxicity. Collectively, these data suggest that p-ERK and its downstream targets, independent of ROS and antioxidant signaling, are important contributors to the cytoprotective effects of ATRA against oncotic cell death.

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LncRNA LINC00342 promotes gastric cancer progression by targeting the miR-545-5p/CNPY2 axis

BMC Cancer ◽

10.1186/s12885-021-08829-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Run Liu ◽

Xianwu Yang

Keyword(s):

Gastric Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Growth Factor Signaling ◽

Ags Cells

Abstract Background This study aimed to explore the role and underlying molecular mechanisms of long non-coding RNA (lncRNA) LINC00342 in gastric cancer (GC). Methods The expression of LINC00342 in GC tissues was evaluated by Quantitative reverse transcription polymerase chain reaction (qRT-PCR). Silencing of LINC00342 was conducted to investigate the effect of LINC00342 in vitro and in vivo. The underlying molecular mechanisms of LINC00342 were determined by dual luciferase reporter assay, Western blotting analysis and rescue experiments. Biological functions of LINC00342 were evaluated by cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay and Transwell assays. In addition, a tumor model was used to verify the effect of LINC00342 in tumorigenesis in vivo. Results LINC00342 was significantly upregulated in GC tissues and cell lines. Silencing of LINC00342 efficiently inhibited proliferation, migration and invasion of AGS cells in vitro, and also suppressed the tumorigenesis of GC in vivo. Functional experiments showed that LINC00342 regulated the expression of canopy fibroblast growth factor signaling regulator 2 (CNPY2) by competitively sponging miR-545-5p. Rescue experiments showed that inhibition of miR-545-5p and overexpression of CNPY2 significantly reversed cell phenotypes caused by silencing of LINC00342. Conclusion LINC00342 plays a potential oncogenic role in GC by targeting the miR545-5p/CNPY2 axis, and might act as a novel therapeutic target for GC.

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CASK Silence Enhances Chemosensitivity of Hepatocellular Carcinoma Through activating Apoptosis, Inducing JNK/c-Jun-Mediated Autophagic Cell Death and Decreasing ABCG2

10.21203/rs.3.rs-152447/v1 ◽

2021 ◽

Author(s):

BiSha Ding ◽

Chang Bao ◽

Luqi Jin ◽

Liang Xu ◽

Zhijun Dai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Drug Resistance ◽

Cell Death ◽

Molecular Mechanisms ◽

Autophagic Cell Death ◽

Cell Counting ◽

Advanced Hepatocellular Carcinoma ◽

Sorafenib Treatment

Abstract Background: Advanced hepatocellular carcinoma (HCC) patients usually fail to be treated because of drug resistance, including sorafenib. Methods: The expression and prognostic role of calcium/calmodulin-dependent serine protein kinase (CASK) in HCC were assessed by combination of bioinformatic analysis and experimental validation. The effects of CASK in regulating proliferation, apoptosis and drug resistance of HCC cells in vitro and in vivo were investigated using gain- or loss-of-function strategies by performing lots of specific methods including Cell Counting kit-8 (CCK8), colony formation assay, flow cytometry, transmission electron microscopy, immunofluorescent confocal laser microscopy and tumor xenograft experiments, immunohistochemistry staining. Moreover, the underlying molecular mechanisms responsible for CASK’s functions in HCC were also explored. Results: Currently, we discovered that CASK was positively associated with sorafenib resistance of HCC in vitro and in vivo, and was significantly related with poor prognosis in HCC. Moreover, inhibition of CASK can increase the effect of sorafenib partially by promoting apoptosis and autophagy, while CASK overexpression presented the opposite results. Besides, all the pan-caspase inhibitor Z-VAD-FMK, autophagy inhibitor 3-Methyladenine (3-MA) and small interfering RNA (siRNA) of LC3B reversed CASK knockout-induced effects with sorafenib treatment, suggesting that both apoptosis and autophagy were involved in CASK-mediated above functions and autophagy played a pro-death role in this research. Intriguingly, similar results were observed in vivo. In molecular level, CASK knockout activated the c-Jun N-terminal kinase (JNK) pathway, and treatment with JNK inhibitor SP600125 or transiently transfected with si-JNK significantly attenuated CASK knockout-mediated autophagic cell death. Besides, knockout of CASK dramatically inhibited the expression of ATP binding cassette subfamily G member 2 (ABCG2) and reversed of multidrug-resistance (MDR) of HCC. Conclusions: Collectively, all these results together indicated that CASK might be a promising biomarker for HCC patients and a potential therapeutic target for relieving drug resistance of HCC.

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HSPA4 knockdown retarded progression and development of colorectal cancer

10.21203/rs.3.rs-54159/v2 ◽

2020 ◽

Author(s):

Mingliang Zhang ◽

Weigang Dai ◽

Zhanyu Li ◽

Liang Tang ◽

Jianhui Chen ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Molecular Therapy ◽

Cell Counting ◽

Antibody Array ◽

And Migration

Abstract Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth most common cause of cancer death. The heat shock 70kDa protein 4 (HSPA4) participate in progression and development of cancers. However, the cellular functions, potential molecular mechanisms of HSPA4 in CRC are still largely unknown. Methods: In this study, qRT-PCR and Western Blot were used to identify the constructed HSPA4 knockdown cell lines, which was further used to construct mouse xenotransplantation models. Effects of HSPA4 knockdown on cell proliferation, apoptotic, cell cycle and migration of CRC were examined using Celigo cell counting assay, Flow cytometry, wound healing assay and Transwell assay, respectively. In addition, Human Apoptosis Antibody Array was performed to explore downstream molecular mechanism of HSPA4 in CRC cells. Results: HSPA4 was overexpressed in CRC, which was positively associated with lymphatic metastasis (N value), number of Lymph node. In addition, high expression of HSPA4 predicted poor prognosis of patients with CRC. Furthermore, HSPA4 knockdown inhibit proliferation, migration, promote apoptosis, and arrest cell cycle of CRC cells in vitro. Moreover, in vivo results supported HSPA4 knockdown inhibit tumor growth. Additionally, the induction of apoptosis of CRC cells by HSPA4 knockdown required the participation of a series of apoptosis-related proteins. The downregulation of HSPA4 promoted the progression of CRC cells, which resulted in alterations of PI3K/Akt, CCND1 and CDK6 in downstream signaling pathways. Conclusions: In sum, the downregulation of HSPA4 promoted CRC and may be a potential target for molecular therapy.

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EGR1/GADD45α Activation by ROS of Non-Thermal Plasma Mediates Cell Death in Thyroid Carcinoma

Cancers ◽

10.3390/cancers13020351 ◽

2021 ◽

Vol 13 (2) ◽

pp. 351

Author(s):

Seung-Nam Jung ◽

Chan Oh ◽

Jae Won Chang ◽

Lihua Liu ◽

Mi Ae Lim ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Apoptotic Cell Death ◽

Promising Alternative ◽

Alternative Treatment Strategy

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) have not been elucidated. (2) Methods: To investigate the mechanism of NTP-induced cell death, THCA cell lines were treated with NTP-activated medium -(NTPAM), and gene expression profiles were evaluated using RNA sequencing. (3) Results: NTPAM upregulated the gene expression of early growth response 1 (EGR1). NTPAM-induced THCA cell death was enhanced by EGR1 overexpression, whereas EGR1 small interfering RNA had the opposite effect. NTPAM-derived reactive oxygen species (ROS) affected EGR1 expression and apoptotic cell death in THCA. NTPAM also induced the gene expression of growth arrest and regulation of DNA damage-inducible 45α (GADD45A) gene, and EGR1 regulated GADD45A through direct binding to its promoter. In xenograft in vivo tumor models, NTPAM inhibited tumor progression of THCA by increasing EGR1 levels. (4) Conclusions: Our findings suggest that NTPAM induces apoptotic cell death in THCA through a novel mechanism by which NTPAM-induced ROS activates EGR1/GADD45α signaling. Furthermore, our data provide evidence that the regulation of the EGR1/GADD45α axis can be a novel strategy for the treatment of THCA.

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