Metabolism-regulated ferroptosis in cancer progression and therapy.

Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with each other to adapt to the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation, which is morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cell death and cuprotosis. Cancer metabolism plays opposite roles in ferroptosis. On the one hand, carbohydrate metabolism can produce NADPH to maintain GPX4 and FSP1 function, and amino acid metabolism can provide substrates for synthesizing GPX4; on the other hand, lipid metabolism might synthesize PUFAs to trigger ferroptosis. The mechanisms through which cancer metabolism affects ferroptosis have been investigated extensively for a long time; however, some mechanisms have not yet been elucidated. In this review, we summarize the interaction between cancer metabolism and ferroptosis. Importantly, we were most concerned with how these targets can be utilized in cancer therapy.

MEK-mediated CHPF2 phosphorylation promotes colorectal cancer cell proliferation and metastasis by activating NF-κB signaling.

The cytokine tumor necrosis factor (TNF) plays a crucial role in the proliferation and metastasis of colorectal cancer (CRC) cells, but the underlying mechanisms remain poorly understood. Here, we report that chondroitin polymerizing factor 2 (CHPF2) promotes CRC cell proliferation and metastasis mediated by TNF, independently of its enzymatic activity. CHPF2 is highly expressed in CRC, and its elevated expression is associated with poor prognosis of CRC patients. Mechanistically, upon TNF stimulation, CHPF2 is phosphorylated at the T588 residue by MEK, enabling CHPF2 to interact with both TAK1 and IKKα. This interaction enhances the binding of TAK1 and IKKα, leading to increased phosphorylation of the IKK complex and activation of NF-κB signaling. As a result, the expression of early growth factors (EGR1) is upregulated to promote CRC cell proliferation and metastasis. In contrast, introduction of a phospho-deficient T588A mutation in CHPF2 weakened the interaction between CHPF2 and TAK1, thus impairing NF-κB signaling. CHPF2 T588A mutation reduced the ability of CHPF2 to promote the proliferation and metastasis of CRC in vitro and in vivo. Furthermore, the NF-κB RELA subunit promotes CHPF2 expression, further amplifying TNF-induced NF-κB signaling activation. These findings identify a moonlighting function of CHPF2 in promoting tumor cell proliferation and metastasis and provide insights into the mechanism by which CHPF2 amplifies TNF-mediated NF-κB signaling activation. Our study provides a molecular basic for the development of therapeutic strategies for CRC treatment.

BcaSOD1 enhances cadmium tolerance in transgenic Arabidopsis by regulating the expression of genes related to heavy metal detoxification and arginine synthesis.

Cadmium (Cd), which is a nonessential heavy metal element for organisms, can have a severe impact on the growth and development of organisms that absorb excessive Cd. Studies have shown that Brassica carinata, a semiwild oil crop, has strong tolerance to various abiotic stresses, and RNA-seq has revealed that the B. carinata superoxide dismutase gene (BcaSOD1) likely responds to Cd stress. To elucidate the BcaSOD1 function involved in tolerance of Cd stress, we cloned the coding sequences of BcaSOD1 from a purple B. carinata accession and successfully transferred it into Arabidopsis thaliana. The subcellular localization results demonstrated that BcaSOD1 was primarily located in the plasma membrane, mitochondria and nucleus. Overexpression of BcaSOD1 in transgenic Arabidopsis (OE) effectively decreased the toxicity caused by Cd stress. Compared to the WT (wild type lines), the OE lines exhibited significantly increased activities of antioxidant enzymes (APX, CAT, POD, and SOD) after exposure to 2.5 mM CdCl2. The Cd content of underground (root) in the OE line was dominantly higher than that in the WT; however, the Cd content of aboveground (shoot) was comparable between the OE and WT types. Moreover, the qRT‒PCR results showed that several heavy metal detoxification-related genes (AtIREG2, AtMTP3, AtHMA3, and AtNAS4) were significantly upregulated in the roots of OE lines under Cd treatment, suggesting that these genes are likely involved in Cd absorption in the roots of OE lines. In addition, both comparable transcriptome and qRT-PCR analyses revealed that exogenous BcaSOD1 noticeably facilitates detoxification by stimulating the expression of two arginine (Arg) biosynthesis genes (AtGDH1 and AtGDH2) while inhibiting the expression of AtARGAH1, a negative regulator in biosynthesis of Arg. The Arg content was subsequently confirmed to be significantly enhanced in OE lines under Cd treatment, indicating that BcaSOD1 likely strengthened Cd tolerance by regulating the expression of Arg-related genes. This study demonstrates that BcaSOD1 can enhance Cd tolerance and reveals the molecular mechanism of this gene, providing valuable insights into the molecular mechanism of Cd tolerance in plants.

Co-Expression Network Analysis of the Transcriptome Identified Hub Genes and Pathways Responding to Saline-Alkaline Stress in Sorghum bicolor L.

Soil salinization, an intractable problem, is becoming increasingly serious and threatening fragile natural ecosystems and even the security of human food supplies. Sorghum (Sorghum bicolor L.) is one of the main crops growing in salinized soil. However, the tolerance mechanisms of sorghum to saline-alkaline soil are still ambiguous. In this study, RNA sequencing was carried out to explore the gene expression profiles of sorghum treated with sodium bicarbonate (150 mM, pH = 8.0, treated for 0, 6, 12 and 24 h). The results show that 6045, 5122, 6804, 7978, 8080 and 12,899 differentially expressed genes (DEGs) were detected in shoots and roots after 6, 12 and 24 h treatments, respectively. GO, KEGG and weighted gene co-expression analyses indicate that the DEGs generated by saline-alkaline stress were primarily enriched in plant hormone signal transduction, the MAPK signaling pathway, starch and sucrose metabolism, glutathione metabolism and phenylpropanoid biosynthesis. Key pathway and hub genes (TPP1, WRKY61, YSL1 and NHX7) are mainly related to intracellular ion transport and lignin synthesis. The molecular and physiological regulation processes of saline-alkali-tolerant sorghum are shown by these results, which also provide useful knowledge for improving sorghum yield and quality under saline-alkaline conditions.

Integrative Physiological and Transcriptome Analysis Reveals the Mechanism of Cd Tolerance in Sinapis alba.

Recently, pollution caused by the heavy metal Cd has seriously affected the environment and agricultural crops. While Sinapis alba is known for its edible and medicinal value, its tolerance to Cd and molecular response mechanism remain unknown. This study aimed to analyze the tolerance of S. alba to Cd and investigate its molecular response mechanism through transcriptomic and physiological indicators. To achieve this, S. alba seedlings were treated with different concentrations of CdCl2 (0.25 mmol/L, 0.5 mmol/L, and 1.0 mmol/L) for three days. Based on seedling performance, S. alba exhibited some tolerance to a low concentration of Cd stress (0.25 mmol/L CdCl2) and a strong Cd accumulation ability in its roots. The activities and contents of several antioxidant enzymes generally exhibited an increase under the treatment of 0.25 mmol/L CdCl2 but decreased under the treatment of higher CdCl2 concentrations. In particular, the proline (Pro) content was extremely elevated under the 0.25 and 0.5 mmol/L CdCl2 treatments but sharply declined under the 1.0 mmol/L CdCl2 treatment, suggesting that Pro is involved in the tolerance of S. alba to low concentration of Cd stress. In addition, RNA sequencing was utilized to analyze the gene expression profiles of S. alba exposed to Cd (under the treatment of 0.25 mmol/L CdCl2). The results indicate that roots were more susceptible to disturbance from Cd stress, as evidenced by the detection of 542 differentially expressed genes (DEGs) in roots compared to only 37 DEGs in leaves. GO and KEGG analyses found that the DEGs induced by Cd stress were primarily enriched in metabolic pathways, plant hormone signal transduction, and the biosynthesis of secondary metabolites. The key pathway hub genes were mainly associated with intracellular ion transport and cell wall synthesis. These findings suggest that S. alba is tolerant to a degree of Cd stress, but is also susceptible to the toxic effects of Cd. Furthermore, these results provide a theoretical basis for understanding Cd tolerance in S. alba.

Overexpression of ApHIPP26 from the Hyperaccumulator Arabis paniculata Confers Enhanced Cadmium Tolerance and Accumulation to Arabidopsis thaliana.

Cadmium (Cd) is a toxic heavy metal that seriously affects metabolism after accumulation in plants, and it also causes adverse effects on humans through the food chain. The HIPP gene family has been shown to be highly tolerant to Cd stress due to its special domain and molecular structure. This study described the Cd-induced gene ApHIPP26 from the hyperaccumulator Arabis paniculata. Its subcellular localization showed that ApHIPP26 was located in the nucleus. Transgenic Arabidopsis overexpressing ApHIPP26 exhibited a significant increase in main root length and fresh weight under Cd stress. Compared with wild-type lines, Cd accumulated much more in transgenic Arabidopsis both aboveground and underground. Under Cd stress, the expression of genes related to the absorption and transport of heavy metals underwent different changes in parallel, which were involved in the accumulation and distribution of Cd in plants, such as AtNRAMP6 and AtNRAMP3. Under Cd stress, the activities of antioxidant enzymes (superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase) in the transgenic lines were higher than those in the wild type. The physiological and biochemical indices showed that the proline and chlorophyll contents in the transgenic lines increased significantly after Cd treatment, while the malondialdehyde (MDA) content decreased. In addition, the gene expression profile analysis showed that ApHIPP26 improved the tolerance of Arabidopsis to Cd by regulating the changes of related genes in plant hormone signal transduction pathway. In conclusion, ApHIPP26 plays an important role in cadmium tolerance by alleviating oxidative stress and regulating plant hormones, which provides a basis for understanding the molecular mechanism of cadmium tolerance in plants and provides new insights for phytoremediation in Cd-contaminated areas.

Fatty acids in cancer chemoresistance.

Despite the remarkable clinical success of immunotherapy and molecular targeted therapy in patients with advanced tumors, chemotherapy remains the most commonly used treatment for most tumor patients. Chemotherapy drugs effectively inhibit tumor cell proliferation and survival through their remarkable mechanisms. However, tumor cells often develop severe intrinsic and acquired chemoresistance under chemotherapy stress, limiting the effectiveness of chemotherapy and leading to treatment failure. Growing evidence suggests that alterations in lipid metabolism may be implicated in the development of chemoresistance in tumors. Therefore, in this review, we provide a comprehensive overview of fatty acid metabolism and its impact on chemoresistance mechanisms. Additionally, we discuss the potential of targeting fatty acid metabolism as a therapeutic strategy to overcome drug resistance.

The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity.

Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.

Tanshinone IIA Suppresses Proliferation and Inflammatory Cytokine Production of Synovial Fibroblasts from Rheumatoid Arthritis Patients Induced by TNF-α and Attenuates the Inflammatory Response in AIA Mice.

Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disease in which activated RA fibroblast-1ike synoviocytes (RA-FLSs) are one of the main factors responsible for inducing morbidity. Previous reports have shown that RA-FLSs have proliferative features similar to cancer cells, in addition to causing cartilage erosion that eventually causes joint damage. Thus, new therapeutic strategies and drugs that can effectively contain the abnormal hyperplasia of RA-FLSs and restrain RA development are necessary for the treatment of RA. Tanshinone IIA (Tan IIA), one of the main phytochemicals isolated from Salvia miltiorrhiza Bunge, is capable of promoting RA-FLS apoptosis and inhibiting arthritis in an AIA mouse model. In addition, RA patients treated at our clinic with Tan IIA showed significant improvements in their clinical symptoms. However, the details of the molecular mechanism by which Tan IIA effects RA are unknown. To clarify this mechanism, we evaluated the antiproliferative and inhibitory effects of proinflammatory factor production caused by Tan IIA to RA-FLSs. We demonstrated that Tan IIA can restrict the proliferation, migration, and invasion of RA-FLSs in a time- and dose-dependent manner. Moreover, Tan IIA effectively suppressed the increase in mRNA expression of some matrix metalloproteinases and proinflammatory factors induced by TNF-α in RA-FLSs, resulting in inflammatory reactivity inhibition and blocking the destruction of the knee joint. Through the integration of network pharmacology analyses with the experimental data obtained, it is revealed that the effects of Tan IIA on RA can be attributed to its influence on different signaling pathways, including MAPK, AKT/mTOR, HIF-1, and NF-kB. Taken together, these data suggest that the compound Tan IIA has great therapeutic potential for RA treatment.