Mitochondrial stress response and myogenic differentiation.

Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases.

Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response.

Drug resistance remains a challenge in ovarian cancer. In addition to aberrant activation of relevant signaling pathways, the adaptive stress response is emerging as a new spotlight of drug resistance in cancer cells. Stress granules (SGs) are one of the most important features of the adaptive stress response, and there is increasing evidence that SGs promote drug resistance in cancer cells. In the present study, we compared two types of ovarian cancer cells, A2780 and SKOV3, using the dual PI3K/mTOR inhibitor, PKI-402. We found that SGs were formed and SGs could intercept the signaling factor ATF5 and regulate the mitochondrial unfolded protein response (UPRmt) in A2780 cells. Therefore, exploring the network formed between SGs and membrane-bound organelles, such as mitochondria, which may provide a new insight into the mechanisms of antitumor drug functions.

RNA binding protein: coordinated expression between the nuclear and mitochondrial genomes in tumors.

Mitochondria are the only organelles regulated by two genomes. The coordinated translation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), which together co-encode the subunits of the oxidative phosphorylation (OXPHOS) complex, is critical for determining the metabolic plasticity of tumor cells. RNA-binding protein (RBP) is a post-transcriptional regulatory factor that plays a pivotal role in determining the fate of mRNA. RBP rapidly and effectively reshapes the mitochondrial proteome in response to intracellular and extracellular stressors, mediating the cytoplasmic and mitochondrial translation balance to adjust mitochondrial respiratory capacity and provide energy for tumor cells to adapt to different environmental pressures and growth needs. This review highlights the ability of RBPs to use liquid-liquid phase separation (LLPS) as a platform for translation regulation, integrating nuclear-mitochondrial positive and retrograde signals to coordinate cross-department translation, reshape mitochondrial energy metabolism, and promote the development and survival of tumor cells.

Highly hydrostable and flexible opal photonic crystal film for enhanced up-conversion fluorescence sensor of COVID-19 antibody.

Efficient detection of related markers is significant for the early screening of COVID-19. Near infrared (NIR) light excited up-conversion fluorescence probes are ideal for biosensing but limited by the low luminescence efficiency. In this work, a novel highly stable opal photonic crystal (OPC) structure was designed to provide an OPC effect for up-conversion fluorescence enhancement, and sensitive Novel Coronavirus IgG up-conversion FRET-based sensor was further constructed. For the problems of water stability and mechanical stability of polymer OPC which cannot be solved for a long time, polymer spray combined with a flipped OPC film strategy is presented. Fragmented size OPC film was firmly fixed by polymer modification layer, which gave large size OPC film great water stability, mechanical stability and bending performance without affecting the fluorescence enhancement property. On this basis, the up-conversion emission intensity was enhanced significantly, and fluorescence resonant energy transfer (FRET) based Novel Coronavirus IgG antibody sensor was constructed. Monolayer up-conversion nanoparticles (UCNPs) on the surface of the polydopamine (PDA)/OPC film can make the fluorescent signal more sensitive, and effectively reduce the detection limit. The test device integrating NIR excitation and mobile phone realized the visual fast detection, showing remarkable sensing performance for COVID-19 antibodies with the limit of detection (LOD) of 0.1 ng mL-1. This detection platform will provide a more effective tool for early detection of the novel coronavirus.

Inhibition of High-Temperature Requirement Protein A2 Protease Activity Represses Myogenic Differentiation via UPRmt.

Skeletal muscles require muscle satellite cell (MuSC) differentiation to facilitate the replenishment and repair of muscle fibers. A key step in this process is called myogenic differentiation. The differentiation ability of MuSCs decreases with age and can result in sarcopenia. Although mitochondria have been reported to be involved in myogenic differentiation by promoting a bioenergetic remodeling, little is known about the interplay of mitochondrial proteostasis and myogenic differentiation. High-temperature-requirement protein A2 (HtrA2/Omi) is a protease that regulates proteostasis in the mitochondrial intermembrane space (IMS). Mice deficient in HtrA2 protease activity show a distinct phenotype of sarcopenia. To investigate the role of IMS proteostasis during myogenic differentiation, we treated C2C12 myoblasts with UCF101, a specific inhibitor of HtrA2 during differentiation process. A key step in this process is called myogenic differentiation. The differentiation ability of MuSCs decreases with age and can result in sarcopenia. Further, CHOP, p-eIF2α, and other mitochondrial unfolded protein response (UPRmt)-related proteins are upregulated. Therefore, we suggest that imbalance of mitochondrial IMS proteostasis acts via a retrograde signaling pathway to inhibit myogenic differentiation via the UPRmt pathway. These novel mechanistic insights may have implications for the development of new strategies for the treatment of sarcopenia.

Systematic Identification of Genomic Markers for Guiding Iron Oxide Nanoparticles in Cervical Cancer Based on Translational Bioinformatics.

Purpose: Magnetic iron oxide nanoparticle (MNP) drug delivery system is a novel promising therapeutic option for cancer treatment. Material issues such as fabrication and functionalized modification have been investigated; however, pharmacologic mechanisms of bare MNPs inside cancer cells remain obscure. This study aimed to explore a systems pharmacology approach to understand the reaction of the whole cell to MNPs and suggest drug selection in MNP delivery systems to exert synergetic or additive anti-cancer effects. Methods: HeLa and SiHa cell lines were used to estimate the properties of bare MNPs in cervical cancer through 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and enzyme activity assays and cellular fluorescence imaging. A systems pharmacology approach was utilized by combining bioinformatics data mining with clinical data analysis and without a predefined hypothesis. Key genes of the MNP onco-pharmacologic mechanism in cervical cancer were identified and further validated through transcriptome analysis with quantitative reverse transcription PCR (qRT-PCR). Results: Low cytotoxic activity and cell internalization of MNP in HeLa and SiHa cells were observed. Lysosomal function was found to be impaired after MNP treatment. Protein tyrosine kinase 2 beta (PTK2B), liprin-alpha-4 (PPFIA4), mothers against decapentaplegic homolog 7 (SMAD7), and interleukin (IL) 1B were identified as key genes relevant for MNP pharmacology, clinical features, somatic mutation, and immune infiltration. The four key genes also exhibited significant correlations with the lysosome gene set. The qRT-PCR results showed significant alterations in the expression of the four key genes after MNP treatment in HeLa and SiHa cells. Conclusion: Our research suggests that treatment of bare MNPs in HeLa and SiHa cells induced significant expression changes in PTK2B, PPFIA4, SMAD7, and IL1B, which play crucial roles in cervical cancer development and progression. Interactions of the key genes with specific anti-cancer drugs must be considered in the rational design of MNP drug delivery systems.

p62 Promotes the Mitochondrial Localization of p53 through Its UBA Domain and Participates in Regulating the Sensitivity of Ovarian Cancer Cells to Cisplatin.

Chemotherapeutic drug-induced p53-dependent crosstalk among tumor cells affects the sensitivity of tumor cells to chemotherapeutic drugs, contributing to chemoresistance. Therefore, pharmacological targeting of p53 may contribute to overcoming drug resistance. The localization of p53 is closely related to its function. Thus, we assessed the effect of p62 on the coordination of p53 mitochondrial localization under chemotherapeutic drug treatment in ovarian cancer cells. We found that the combined use of the proteasome inhibitor epoxomicin and cisplatin led to the accumulation of p53 and sequestosome1(p62) in the mitochondria, downregulated mitochondrial DNA (mtDNA) transcription, inhibited mitochondrial functions, and ultimately promoted apoptosis by enhancing cisplatin sensitivity in ovarian cancer cells. Moreover, the ubiquitin-associated (UBA) domain of p62 was involved in regulating the mitochondrial localization of p53. Our findings suggest that the interaction between p62 and p53 may be a mechanism that determines the fate of tumor cells. In conclusion, p62 coordinated the mitochondrial localization of p53 through its UBA domain, inhibited mtDNA transcription, downregulated mitochondrial function, and promoted ovarian cancer cell death. Our study demonstrates the important role of p53 localization in tumor cell survival and apoptosis, and provides new insights into understanding the anti-tumor mechanism of targeting the ubiquitin-proteasome system in tumor cells.

Erratum: MiR-216a-5p inhibits tumorigenesis in Pancreatic Cancer by targeting TPT1/mTORC1 and is mediated by LINC01133: Erratum.

[This corrects the article DOI: 10.7150/ijbs.46822.].

The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer.

Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer.

Adaptive Changes Allow Targeting of Ferroptosis for Glioma Treatment.

Ferroptosis is a type of regulated cell death that plays an essential role in various brain diseases, including cranial trauma, neuronal diseases, and brain tumors. It has been reported that cancer cells rely on their robust antioxidant capacity to escape ferroptosis. Therefore, ferroptosis exploitation could be an effective strategy to prevent tumor proliferation and invasion. Glioma is a common malignant craniocerebral tumor exhibiting complicated drug resistance and survival mechanisms, resulting in a high mortality rate and short survival time. Recent studies have determined that metabolic alterations in glioma offer exploitable therapeutic targets. These metabolic alterations allow targeted therapy to achieve some initial efficacy but have failed to inhibit glioma growth, invasion, and drug resistance effectively. It has been proposed that the reason for the high malignancy and drug resistance observed with glioma is that these tumors can effectively evade ferroptosis. Ferroptosis-inducing drugs were found to exert a positive effect by targeting this particular characteristic of glioma cells. Moreover, gliomas develop enhanced drug resistance through anti-ferroptosis mechanisms. In this study, we provided an overview of the mechanisms by which glioma aggressiveness and drug resistance are mediated by the evasion of ferroptosis. This information might provide new targets for glioma therapy as well as new insights and ideas for future research.

PGC-1α protects from myocardial ischaemia-reperfusion injury by regulating mitonuclear communication.

The recovery of blood supply after a period of myocardial ischaemia does not restore the heart function and instead results in a serious dysfunction called myocardial ischaemia-reperfusion injury (IRI), which involves several complex pathophysiological processes. Mitochondria have a wide range of functions in maintaining the cellular energy supply, cell signalling and programmed cell death. When mitochondrial function is insufficient or disordered, it may have adverse effects on myocardial ischaemia-reperfusion and therefore mitochondrial dysfunction caused by oxidative stress a core molecular mechanism of IRI. Peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) is an important antioxidant molecule found in mitochondria. However, its role in IRI has not yet been systematically summarized. In this review, we speculate the role of PGC-1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like -1 and -2 (NRF-1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.

Serine protease HtrA2/Omi regulates adaptive mitochondrial reprogramming in the brain cortex after ischemia/reperfusion injury via UCP2-SIRT3-PGC1 axis.

This study is to investigate the underlying mechanisms of mitochondrial quality control (MQC) regulated by HtrA2/Omi during ischemia/reperfusion (I/R). We utilized the mnd2 mouse model, which has a missense mutation in HtrA2/Omi, to investigate the HtrA2/Omi regulation in mitochondria after I/R injury in the cerebral cortex. Compared to homozygous (HtrA2mnd2) mice, heterozygous (HtrA2Hetero) mice showed aging signs at a later age, increased HtrA2/Omi expression in the brain cortex, and lesser neurodegenerative signs. The brain cortex of HtrA2Hetero mice had increased superoxide dismutase (SOD) activity; lower levels of malondialdehyde (MDA); higher expressions of mitochondrial unfolded protein response (mtUPR)-related proteins, NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (Ndufs7), and uncoupling protein 2 (UCP2) proteins; more mitochondrial fission; higher levels of ATP and mtDNA copies; elevated sirtuin 3 (SIRT3) activity; and increased NAD+/NADH ratio. After 1.5 h of I/R, the brain cortex of HtrA2Hetero mice had a larger infarction size, reduced HtrA2/Omi expression, decreased S-X-linked inhibitor of apoptosis protein (XIAP), and increased C-Caspase3 than that of wild-type animals (WT). Mitochondria from the HtrA2Hetero brain cortex showed decreased ATP production and MQC deficiency after 1.5 h I/R. Genipin pre-treatment reduced the aforementioned I/R injury in the HtrA2Hetero brain cortex. In conclusion, mitochondrial function is compensated in the HtrA2Hetero brain cortex via the upregulation of the UCP2-SIRT3-PGC1 axis. Decreased HtrA2/Omi function damages mitochondrial quality in the HtrA2Hetero mouse brain cortex, leading to more brain I/R injury. Genipin pre-treatment ameliorates brain damages via the mitochondrial UCP2-SIRT3-PGC1 axis.

Suppressing TRAP1 sensitizes glioblastoma multiforme cells to temozolomide.

Glioma is a common malignant tumor of the central nervous system, accounting for ~50% of intracranial tumors. The current standard therapy for glioma is surgical resection followed by postoperative adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. However, resistance to TMZ is one of the factors affecting prognosis. It has been reported that TNF receptor-associated protein 1 (TRAP1) is overexpressed in numerous types of tumor and that interfering with its function may abrogate chemotherapy resistance. TRAP1 inhibitor Gamitrinib triphenylphosphonium (G-TPP) and shRNA were used in the present study to suppress the function of this molecule in glioblastoma multiforme (GBM) cell lines. MTT assay was performed to evaluate the combined effect of G-TPP and TMZ treatment. To investigate the underlying mechanism responsible for this combined effect, the mitochondrial unfolded protein response (mtUPR), mitophagy, mitochondrial fusion and reactive oxygen species (ROS) were quantified using western blotting and immunofluorescence techniques. TMZ treatment induced apoptosis in GBM cells by activating the p53 pathway, whilst simultaneously downregulating mitophagy and enhancing mitochondrial fusion. The latter may occur in order to compensate for the defect caused by downregulated mitophagy. Suppressing the function of TRAP1 disturbed this compensatory mechanism by inducing mtUPR, which resulted in a burst of ROS formation and sensitized the GBM cells to the effects of TMZ treatment. Thus, suppressing the function of TRAP1 sensitized GBM cells to TMZ lysis by inducing mtUPR and the subsequent ROS burst. TRAP1 is therefore considered to be a promising target for GBM therapy.

PGC1α Promotes Cisplatin Resistance in Ovarian Cancer by Regulating the HSP70/HK2/VDAC1 Signaling Pathway.

Mitochondrial apoptosis is one of the main mechanisms for cancer cells to overcome chemoresistance. Hexokinase 2 (HK2) can resist cancer cell apoptosis by expressing on mitochondria and binding to voltage-dependent anion channel 1 (VDAC1). We previously reported that peroxisome proliferator-activated receptor coactivator 1 α (PGC1α) is highly expressed in ovarian cancer cisplatin-resistant cells. However, the underlying mechanism remains unclear. Therefore, we evaluated the interaction between PGC1α and HK2 in ovarian cancer cisplatin-resistant cells. We found that the knockdown of PGC1α promotes the apoptosis of ovarian cancer cisplatin-resistant cells and increases their sensitivity to cisplatin. In addition, we found that the knockdown of PGC1α affects the mitochondrial membrane potential and the binding of HK2 and VDAC1. As the heat shock protein 70 (HSP70) family can help protein transport, we detected it and found that PGC1α can promote HSP70 gene transcription. Furthermore, HSP70 can promote an increase of HK2 expression on mitochondria and an increase of binding to VDAC1. Based on these results, PGC1α may reduce apoptosis through the HSP70/HK2/VDAC1 signaling pathway, thus promoting cisplatin resistance of ovarian cancer. These findings provide strong theoretical support for PGC1α as a potential therapeutic target of cisplatin resistance in ovarian cancer.

The MAMs Structure and Its Role in Cell Death.

The maintenance of cellular homeostasis involves the participation of multiple organelles. These organelles are associated in space and time, and either cooperate or antagonize each other with regards to cell function. Crosstalk between organelles has become a significant topic in research over recent decades. We believe that signal transduction between organelles, especially the endoplasmic reticulum (ER) and mitochondria, is a factor that can influence the cell fate. As the cellular center for protein folding and modification, the endoplasmic reticulum can influence a range of physiological processes by regulating the quantity and quality of proteins. Mitochondria, as the cellular "energy factory," are also involved in cell death processes. Some researchers regard the ER as the sensor of cellular stress and the mitochondria as an important actuator of the stress response. The scientific community now believe that bidirectional communication between the ER and the mitochondria can influence cell death. Recent studies revealed that the death signals can shuttle between the two organelles. Mitochondria-associated membranes (MAMs) play a vital role in the complex crosstalk between the ER and mitochondria. MAMs are known to play an important role in lipid synthesis, the regulation of Ca2+ homeostasis, the coordination of ER-mitochondrial function, and the transduction of death signals between the ER and the mitochondria. Clarifying the structure and function of MAMs will provide new concepts for studying the pathological mechanisms associated with neurodegenerative diseases, aging, and cancers. Here, we review the recent studies of the structure and function of MAMs and its roles involved in cell death, especially in apoptosis.

An Experimentally Induced Mutation in the UBA Domain of p62 Changes the Sensitivity of Cisplatin by Up-Regulating HK2 Localisation on the Mitochondria and Increasing Mitophagy in A2780 Ovarian Cancer Cells.

The study of cisplatin sensitivity is the key to the development of ovarian cancer treatment strategies. Mitochondria are one of the main targets of cisplatin, its self-clearing ability plays an important role in determining the fate of ovarian cancer cells. First, we proved that the sensitivity of ovarian cancer cells to cisplatin depends on mitophagy, and p62 acts as a broad autophagy receptor to regulate this process. However, p62's regulation of mitophagy does not depend on its location on the mitochondria. Our research shows that the mutation of the UBA domain of p62 increases the localisation of HK2 on the mitochondria, thereby increasing the phosphorylated ubiquitin form of parkin, then stabilising the process of mitophagy and ultimately cell survival. Collectively, our results showed that a mutation in the UBA domain of p62 regulates the level of apoptosis stimulated by cisplatin in ovarian cancer.

The IL-33/ST2 axis affects tumor growth by regulating mitophagy in macrophages and reprogramming their polarization.

Objective: Macrophages are a major component of the tumor microenvironment. M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development, whereas tumor-associated macrophages (TAMs) mainly exhibit an M2 phenotype. Our previous studies have shown that the interleukin-33/ST2 (IL-33/ST2) axis is essential for activation of the M1 phenotype. This study investigates the role of the IL-33/ST2 axis in TAMs, its effects on tumor growth, and whether it participates in the mutual conversion between the M1 and M2 phenotypes. Methods: Bone marrow-derived macrophages were extracted from wildtype, ST2 knockout (ST2-/-), and Il33-overexpressing mice and differentiated with IL-4. The mitochondrial and lysosomal number and location, and the expression of related proteins were used to analyze mitophagy. Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes. Results: The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels. The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation, thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth (P < 0.05) (Figure 4). This metabolic shift was not due to mitochondrial damage, because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout; however, it might be associated with the mTOR activity. Conclusions: These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization, and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.

Mitochondrial integration and ovarian cancer chemotherapy resistance.

Ovarian cancer has been nicknamed the "silent killer". Most patients with ovarian cancer are diagnosed at an advanced stage of the disease for the first time because of its insignificant early clinical symptoms. In addition to the difficulty of early screening and delay in diagnosis, the high recurrence rate and relapsed refractory status of patients with ovarian cancer are also important factors for their high mortality. Patients with recurrent ovarian cancer often use neoadjuvant chemotherapy followed by surgery as the first choice. However, this is often accompanied by chemotherapy resistance, leading to treatment failure and a mortality rate of more than 90%. In the past, it was believed that the anti-tumor effect of chemotherapeutics represented by cisplatin was entirely attributable to its irreversible damage to DNA, but current research has found that it can inhibit cell growth and cytotoxicity via nuclear and cytoplasmic coordinated integration. As an important hub and integration platform for intracellular signal communication, mitochondria are responsible for multiple key factors during tumor occurrence and development, such as metabolic reprogramming, acquisition of metastatic ability, and chemotherapy drug response. The role of mitochondria in ovarian cancer chemotherapy resistance is becoming increasingly recognized. In this review, we discuss the cellular interactive regulatory network surrounding mitochondria, elucidate the mechanisms of tumor cell survival under chemotherapy, and discuss potential means of interfering with mitochondrial function as a novel anti-cancer therapy.

p53 Promoted Ferroptosis in Ovarian Cancer Cells Treated with Human Serum Incubated-Superparamagnetic Iron Oxides.

METHODS: In this study, we used MTT assays to demonstrate that a combination of SPIO-Serum and wild-type p53 overexpression can reduce ovarian cancer cell viability in vitro. Prussian blue staining and iron assays were used to determine changes in intracellular iron concentration following SPIO-Serum treatment. TEM was used to evaluate any mitochondrial damage induced by SPIO-Serum treatment, and Western blot was used to evaluate the expression of the iron transporter and lipid peroxidation regulator proteins. JC-1 was used to measure mitochondrial membrane potential, and ROS levels were estimated by flow cytometry. Finally, xCT protein expression and mitochondrial ROS levels were confirmed using fluorescence microscopy. RESULTS: SPIO-Serum effectively induced lipid peroxidation and generated abundant toxic ROS. It also facilitated the downregulation of GPX4 and xCT, ultimately resulting in iron-dependent oxidative death. These effects could be reversed by iron chelator DFO and lipid peroxidation inhibitor Fer-1. SPIO-Serum treatment disrupted intracellular iron homeostasis by regulating iron uptake and the cells presented with missing mitochondrial cristae and ruptured outer mitochondrial membranes. Moreover, we were able to show that p53 contributed to SPIO-Serum-induced ferroptosis in ovarian cancer cells. CONCLUSION: SPIO-Serum induced ferroptosis and overexpressed p53 contributed to ferroptosis in ovarian cancer cells. Our data provide a theoretical basis for ferroptosis as a novel cell death phenotype induced by nanomaterials.

Polyphyllin VII induces mitochondrial apoptosis by regulating the PP2A/AKT/DRP1 signaling axis in human ovarian cancer.

Ovarian cancer is a gynecological malignancy with high mortality. Adjuvant therapy such as chemoradiotherapy inevitably leads to side effects and drug resistance. In recent years, traditional Chinese medicine has been widely studied for its safety, effectiveness, and unique pharmacological effects. Polyphyllin VII is an important component of Rhizoma paridis saponins, and has cytotoxic effects on many types of cancer cells. The aim of the present study was to evaluate the anti­tumor activity of polyphyllin VII in human ovarian cancer cells. Recent studies found that polyphyllin VII induces mitochondrial pathway apoptosis by increasing mitochondrial division, but the specific mechanism was unclear. The results of this study revealed that polyphyllin VII could effectively induce mitochondrial dysfunction, including increased mitochondrial division and reactive oxygen species (ROS) production. Notably, the mitochondrial location of dynamin­related protein 1 (DRP1) plays an important role in its function. In addition, polyphyllin VII enhanced the mitochondrial localization of DRP1 which is mediated by increased protein phosphatase 2A (PP2A) activity, and decreased AKT activity. A specific PP2A inhibitor, LB100, attenuated mitochondrial division and apoptosis in cells caused by polyphyllin VII, confirming the function of the PP2A/AKT pathway in polyphyllin VII treatment. Additionally, xenotransplantation experiments have also confirmed the anti­tumor effect of polyphyllin VII in vivo. Therefore, interference of the mitochondrial translocation of DRP1 through PP2A/AKT pathway may be an attractive and effective therapeutic approach by polyphyllin VII in ovarian cancer. This may provide new strategies for polyphyllin VII in the clinical treatment of ovarian cancer.