Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.

Protective Behaviors Against COVID-19 and Related Factors in Korean Adults With Depressive Symptoms: Results From an Analysis of the 2020 Korean Community Health Survey.

OBJECTIVE: This study evaluated protective behaviors against coronavirus disease-2019 (COVID-19) and related factors in individuals with depressive symptoms. METHODS: This cross-sectional study included data from the 2020 Korean Community Health Survey. Depressive symptoms, COVID- 19 protection behaviors, and related factors were investigated in 228,485 people. Chi-square test and logistic regression analysis were used to analyze categorical variables. Statistical analysis was performed using SPSS software (version 27.0). RESULTS: In the study, 3.9% (n=8,970) had depressive symptoms. The prevalence of depressive symptoms was higher in individuals in their 19-39 years , and ≥60s than in those in their 40-59 years (p<0.001). Lower education level and household income were associated with a higher prevalence of depression (p<0.001). Among the various occupations, service workers had the highest prevalence of depressive symptoms (p<0.001). Individuals with depressive symptoms were less likely to adopt protective behaviors against COVID-19 (p<0.001) or exhibit concerns regarding death and economic damage (p<0.001) compared to individuals without depressive symptoms. Individuals with depressive symptoms were more likely to have unhealthy behaviors than those without depressive symptoms (p<0.001). Individuals with depressive symptoms considered that the COVID-19 response by the government and other organizations was inadequate (p<0.001). CONCLUSION: During the COVID-19 pandemic, individuals with depressive symptoms faced greater challenges in adopting protective behaviors. Therefore, it is crucial to develop strategies to protect people with depressive symptoms during another pandemic in the future.

Validating a Korean Version of the Single-Item Burnout Measure for Evaluating Burnout Among Doctors.

OBJECTIVE: It is essential to measure the effect of burnout on doctors because burnout can affect doctors' mental health as well as the functioning of medical practice. This study aims to validate a Korean version of the single-item burnout measure (SIBM), which was developed to quickly measure the level of burnout among doctors. METHODS: Through an online survey, a self-report questionnaire was administered to 324 public health doctors in Korea. The Korean version of the SIBM was validated against the Maslach Burnout Inventory-General Survey (MBI-GS), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7) screening tool, the Perceived Stress Scale (PSS), and the Vaccination Attitudes Examination (VAX) scale. Pearson correlation coefficients and analysis of variance (ANOVA) were used to determine the association between the SIBM and other scales. ANOVA was additionally used to determine the associations between the subscales of the MBI-GS and those of the SIBM. RESULTS: The correlation coefficient between the SIBM and the MBI-GS, PHQ-9, GAD-7, and PSS was positive (p<0.01), and the correlation coefficient between the SIBM and the VAX scale was not significant. Therefore, convergent and discriminant validity was verified. Exhaustion and cynicism, which were correlated with the SIBM, with r2=0.43 (p<0.01) and 0.48 (p<0.01), yielded R2 scores of 0.27 (p<0.01) and 0.20 (p<0.01) in ANOVA. CONCLUSION: The Korean version of the SIBM is an appropriate screening tool for burnout. It can be evaluated in a short time, thereby enhancing continuous follow-up observations and response rates to burnout.

Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells.

Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as a repurposed drug. We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although the covalent inhibition of thioredoxin reductase (TrxR), an enzyme that critically controls intracellular redox homeostasis, is considered the primary mechanism of AF's anticancer activity, knockdown of TrxR1 did not induce paraptosis. Instead, both TrxR1 knockdown plus the proteasome inhibitor (PI), bortezomib (Bz), and 2 µM AF plus Bz induced paraptosis, thereby mimicking the effect of 5 µM AF. These results suggest that the paraptosis induced by 5 µM AF requires the inhibition of both TrxR1 and proteasome. We found that TrxR1 knockdown/Bz or subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells, whereas 4~5 µM AF killed both cancer and MCF10A cells. GSH depletion was found to be more critical than ROS generation for the paraptosis induced by dual TrxR1/proteasome inhibition. In this process, the ATF4/CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1) axis leads to GSH degradation, contributing to proteotoxic stress possibly due to the accumulation of misfolded thiol-containing proteins. These results suggest that the paraptosis-inducing strategy of AF plus a PI may provide an effective therapeutic strategy against pro-apoptotic therapy-resistant cancers and reduce the potential side effects associated with high-dose AF.

The effects of sociodemographic factors on help-seeking for depression: Based on the 2017-2020 Korean Community Health Survey.

When individuals face psychological difficulties that exceed their resources, consulting professionals for mental health treatment can be an effective way to overcome these difficulties. However, in general, only a few patients receive treatment for depression. The goal of the present study was to explore the help-seeking behaviors of currently employed individuals with depression and the factors influencing their help-seeking behaviors. This study used raw data from the Korean Community Health Survey (KCHS) obtained from 2017 to 2020. A total of 6,505 employed individuals, who responded as having experiences of sadness or hopelessness that caused problems in their lives for more than two weeks and who scored more than nine points on the Patient Health Questionnaire-9, were included in our analysis. Help-seeking behavior was measured as receiving expert advice due to feelings of sadness or hopelessness. Of the 6,505 people with depression, only 1,781 (27.38%) received professional counseling for it. Male participants (adjusted odds ratio [aOR] = 1.31, 95% confidence interval [CI] = 1.157-1.487), those aged 45-64 years (aOR = 1.192, 95% CI = 1.022-1.389) and more than 75 years (aOR = 1.446, 95% CI = 1.059-1.973), those not having a Medical Aid program (aOR = 1.750, 95% CI = 1.375-2.226), and those having low educational levels (aOR = .896, 95% CI = .830-.968) were less likely to seek professional help for depression. Our study found that help-seeking behaviors for depression in the Korean population were low. Furthermore, we identified the characteristics associated with individuals with depressive symptoms who chose not to receive help from mental health professionals. The results of this study provide insights to guide national interventions to increase help-seeking behaviors for depression.

Curcumin inhibits the cancer­associated fibroblast­derived chemoresistance of gastric cancer through the suppression of the JAK/STAT3 signaling pathway.

The present study aimed to investigate whether the Janus­activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a critical mechanism underlying the cancer­associated fibroblast (CAF)­induced chemoresistance of gastric cancer (GC). In addition, the present study tried to suggest a natural product to compromise the effects of CAF on the chemoresistance of GC. The results of cell proliferation assay revealed that the conditioned medium (CM) collected from CAFs further increased resistance to 5­fluorouracil (5­FU) in GC cell lines. Secretome analysis revealed that the levels of several secreted proteins, including C­C motif chemokine ligand 2, C­X­C motif chemokine ligand 1, interleukin (IL)­6 and IL­8, were increased in the CM from CAFs co­cultured with cancer cells compared to CM from cancer cells. Western blot analysis revealed that CAFs activated the JAK/STAT3 signaling pathway in cancer cells. The experimental models revealed that curcumin abrogated the CAF­mediated activation of the JAK/STAT3 signaling pathway in GC cells. In vivo data revealed the synergistic effects of curcumin with 5­FU treatment in xenograft GC tumors. These data strongly suggest that the suppression of the JAK/STAT3 signaling pathway counteracts the CAF­induced chemoresistance of GC cells. It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF­induced activation of the JAK/STAT3 signaling pathway in GC.

PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance.

PSMD14, a subunit of the 19S regulatory particles of the 26S proteasome, was recently identified as a potential prognostic marker and therapeutic target in diverse human cancers. Here, we show that the silencing and pharmacological blockade of PSMD14 in MDA-MB 435S breast cancer cells induce paraptosis, a non-apoptotic cell death mode characterized by extensive vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. The PSMD14 inhibitor, capzimin (CZM), inhibits proteasome activity but differs from the 20S proteasome subunit-inhibiting bortezomib (Bz) in that it does not induce aggresome formation or Nrf1 upregulation, which underlie Bz resistance in cancer cells. In addition to proteasome inhibition, the release of Ca2+ from the ER into the cytosol critically contributes to CZM-induced paraptosis. Induction of paraptosis by targeting PSMD14 may provide an attractive therapeutic strategy against cancer cells resistant to proteasome inhibitors or pro-apoptotic drugs.

ISRIB plus bortezomib triggers paraptosis in breast cancer cells via enhanced translation and subsequent proteotoxic stress.

Despite the success of proteasome inhibitors (PIs) in treating hematopoietic malignancies, including multiple myeloma (MM), their clinical efficacy is limited in solid tumors. In this study, we investigated the involvement of the integrated stress response (ISR), a central cellular adaptive program that responds to proteostatic defects by tuning protein synthesis rates, in determining the fates of cells treated with PI, bortezomib (Bz). We found that Bz induces ISR, and this can be reversed by ISRIB, a small molecule that restores eIF2B-mediated translation during ISR, in both Bz-sensitive MM cells and Bz-insensitive breast cancer cells. Interestingly, while ISRIB protected MM cells from Bz-induced apoptosis, it enhanced Bz sensitivity in breast cancer cells by inducing paraptosis, the cell death mode that is accompanied by dilation of the endoplasmic reticulum (ER) and mitochondria. Combined treatment with ISRIB and Bz may shift the fate of Bz-insensitive cancer cells toward paraptosis by inducing translational rescue, leading to irresolvable proteotoxic stress.

An Open Pilot Trial of Written Exposure Therapy for Patients With Post-Traumatic Stress Disorder in Korea.

OBJECTIVE: Written exposure therapy (WET) is exposure therapy for post-traumatic stress disorder (PTSD). Compared to evidencebased treatments for PTSD, WET requires only five sessions, has a shorter session time, and no between-session assignments. The current study examined the efficacy of WET among Korean patients with PTSD due to various traumatic events on PTSD symptoms, depressive symptoms, and global functioning levels. METHODS: The study recruited 41 patients with a current primary diagnosis of PTSD in psychiatric outpatient clinics. Assessments were conducted at baseline, and at 6, 12, and 24 weeks following the first treatment session. RESULTS: In total, 25 patients started WET. Findings showed a significant reduction in the rate of PTSD diagnosis and symptom severity scores. Fourteen of 23 (60.9%) patients at 6 weeks, 15 of 22 (68.2%) patients at 12 weeks, and 14 of 18 (77.8%) patients at 24 weeks no longer met the diagnosis of PTSD. Depressive symptoms and global function scores also improved after WET. The dropout rate was 8% (n=2). CONCLUSION: This study suggests the feasibility of implementing WET among various types of patients with PTSD in Korea and other Asian countries.

Posttraumatic stress disorder symptoms and neurocognitive functioning in fire fighters: The mediating role of sleep problems and resilience.

BACKGROUND: Firefighters are often exposed to terrible and dangerous scenes due to their duties, and thus have a high risk of developing posttraumatic stress disorder(PTSD). The purpose of the study is to examine the relationship between PTSD symptoms, sleep problems, resilience and neurocognitive functioning of firefighters, and to identify the sequential mediating effects of sleep problems and resilience on the relationship between PTSD symptoms and neurocognitive functioning (especially psychomotor speed and processing speed). METHODS: Data were collected from 325 firefighters in eight fire departments in four regions of Korea. Subjects performed neurocognitive function tests and completed the following questionnaires: Primary Care PTSD Screening, Pittsburgh Sleep Quality Index-K and Connor-Davidson Resilience Scale-2. The correlation and dual mediation effects were analysed using SPSS 22.0 program and PROCESS macro 3.4 program. RESULTS: PTSD symptoms, neurocognitive functioning, sleep problems and resilience were significantly correlated with each other. In the sequential mediation model, the relationship between PTSD and psychomotor speed/processing speed was sequentially mediated by sleep problems and resilience after adjusting for demographic variables. CONCLUSIONS: The PTSD symptoms of firefighters were related to a sequential link between sleep problems, low resilience and decreased neurocognitive function. These findings could serve as a basis for more effective and integrated interventional strategies for facilitating better neurocognitive functioning in firefighters.

The Interaction of Inflammatory Markers and Alcohol-Use on Cognitive Function in Korean Male Firefighters.

OBJECTIVE: Cognitive functions have been shown to become impaired due to alcoholism. Recently, neuroinflammation gained attention for playing a role in the neurotoxic effect of alcohol. However, there is limited data on the relationship between alcohol and cognitive function, based on the mechanism of inflammation. This study examined whether the interaction between alcohol use and pro-inflammatory biomarkers is related to cognitive function in Korean male firefighters. METHODS: A total of 474 firefighters were assessed for alcohol-related problems using CAGE, cognitive functions, and pro-inflammatory biomarkers (CRP, IL-6, TNF-α). Sequential multiple regression analyses were conducted to determine if inflammatory markers moderate the relationship between alcohol use and cognitive function. RESULTS: Only a decreased attentional function was associated with the interaction of alcohol use and inflammatory markers, after controlling for age, sex, body mass index, lipid profiles, smoking, depression, fatigue, self-reported hypertension, diabetes, and musculoskeletal problems. CONCLUSION: This study revealed that the interaction between alcohol use and inflammation is related to attentional function in Korean male firefighters. Additionally, this cross-sectional study suggests that diminishing attention, related to alcohol use, may be based on the mechanism of inflammation.

Mitochondrial Respiratory Defect Enhances Hepatoma Cell Invasiveness via STAT3/NFE2L1/STX12 Axis.

Mitochondrial respiratory defects have been implicated in cancer progression and metastasis, but how they control tumor cell aggressiveness remains unclear. Here, we demonstrate that a mitochondrial respiratory defect induces nuclear factor-erythroid 2 like 1 (NFE2L1) expression at the transcriptional level via reactive oxygen species (ROS)-mediated STAT3 activation. We identified syntaxin 12 (STX12) as an effective downstream target of NFE2L1 by performing cDNA microarray analysis after the overexpression and depletion of NFE2L1 in hepatoma cells. Bioinformatics analysis of The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) open database (n = 371) also revealed a significant positive association (r = 0.3, p = 2.49 × 10-9) between NFE2L1 and STX12 expression. We further demonstrated that STX12 is upregulated through the ROS/STAT3/NFE2L1 axis and is a key downstream effector of NFE2L1 in modulating hepatoma cell invasiveness. In addition, gene enrichment analysis of TCGA-LIHC also showed that epithelial-mesenchymal transition (EMT)-related core genes are significantly upregulated in tumors co-expressing NFE2L1 and STX12. The positive association between NFE2L1 and STX12 expression was validated by immunohistochemistry of the hepatocellular carcinoma tissue array. Finally, higher EMT gene enrichment and worse overall survival (p = 0.043) were observed in the NFE2L1 and STX12 co-expression group with mitochondrial defect, as indicated by low NDUFA9 expression. Collectively, our results indicate that NFE2L1 is a key mitochondrial retrograde signaling-mediated primary gene product enhancing hepatoma cell invasiveness via STX12 expression and promoting liver cancer progression.

Association between Shift Work and Neurocognitive Function among Firefighters in South Korea: A Prospective Before-After Study.

Background: Recent research indicates that shift work is associated with neurocognitive function. However, studies that examine the association between shift work and neurocognitive function in firefighters have not yet been performed. We examined the effect of shift work on neurocognitive function in firefighters by measuring and comparing neurocognitive function before and after night shift. Methods: 352 firefighters from eight fire stations in South Korea were included in this study. We performed neurocognitive function test using central nervous system vital signs (CNSVS) during daytime work and on the next day after night work. We performed paired t-tests to assess differences between neurocognitive function before and after night work. We also compared neurocognitive function in insomnia and depression. We used a general linear model to analyze the associations between shiftwork schedule and the changes in neurocognitive function. Results: The neurocognitive function significantly decreased in six domains (composite memory, verbal memory, visual memory, complex attention, psychomotor speed, and motor speed) as did the neurocognitive index on the next day after night work compared with during day work. These decreased domains were the same following night work regardless of the type of shift work. Conclusion: Night work in firefighters may cause neurocognitive decline.

Screening of Drug-Induced Steatosis and Phospholipidosis Using Lipid Droplet-Selective Two-Photon Probes.

Lipid droplets (LDs) are organelles that play a major role in regulating the storage of neutral lipids. Dysregulation of LDs is associated with metabolic disorders, such as fatty liver diseases, obesity, diabetes, and atherosclerosis. We have developed LD-selective small-molecule fluorescence probes (probes 3 and 4) that are available for both one- and two-photon microscopy, employing live or fixed cells. We found that probes 3 and 4 sensitively detect the increased LDs in response to oleic acid or endoplasmic reticulum stress, both in cells and tissues of the liver. The narrow absorption and emission bands of probes 3 and 4 allow multicolor imaging for the study of the role of LDs in pathophysiology and LD-associated signaling by the coapplication of the probes for different organelles or antibodies against specific proteins. In addition, we show here, for the first time, that two-photon microscopy imaging using our LD-selective probes with LysoTracker provides a novel method for screening drugs to potentially induce steatosis and/or phospholipidosis.

Psychosocial Support during the COVID-19 Outbreak in Korea: Activities of Multidisciplinary Mental Health Professionals.

As of April 18, 2020, there have been a total of 10,653 confirmed cases and 232 deaths due to coronavirus disease 2019 (COVID-19) in Korea. The pathogen spread quickly, and the outbreak caused nationwide anxiety and shock. This study presented the anecdotal records that provided a detailed process of the multidisciplinary teamwork in mental health during the COVID-19 outbreak in the country. Psychosocial support is no less important than infection control during an epidemic, and collaboration and networking are at the core of disaster management. Thus, a multidisciplinary team of mental health professionals was immediately established and has collaborated effectively with its internal and external stakeholders for psychosocial support during the COVID-19 outbreak.

Quercetin and chloroquine synergistically kill glioma cells by inducing organelle stress and disrupting Ca2+ homeostasis.

Glioblastoma (GBM) remains one of the most uncompromising cancers, with a median survival of 15 months among those receiving maximal therapy. Therefore, new effective approaches are urgently required for the treatment of GBM. In this study, we show that combined treatments with the flavonoid quercetin and chloroquine (CQ), which is a lysosomotropic agent with antimalarial activity, synergistically induce caspase-independent cell death in malignant glioma cells. The combination of quercetin and CQ triggered excessive expansion of autolysosomes and lysosomes due to overloading with undigested cellular components and protein aggregates, leading to cell death, whereas quercetin alone increased autophagic flux. These results suggest that CQ-mediated lysosomal inhibition prolongs quercetin-mediated autophagic flux, resulting in autophagic catastrophe and severe endoplasmic reticulum (ER) stress. Additionally, we found that 1,4,5-triphosphate receptor (IP3R)-mediated Ca2+ release from the ER and the following mitochondrial uniporter (MCU)-mediated Ca2+ influx into mitochondria as well as ROS generation are critically involved in the cytotoxicity by this combination. Collectively, the lysosomal defects induced by quercetin plus CQ may trigger the stress to both the ER and mitochondria and consequently their functional defects, contributing to glioma cell death. The combination of quercetin and CQ may be an effective therapeutic option for GBM.

Intracellular Ca2 + Imbalance Critically Contributes to Paraptosis.

Paraptosis is a type of programmed cell death that is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria. Since paraptosis is morphologically and biochemically different from apoptosis, understanding its regulatory mechanisms may provide a novel therapeutic strategy in malignant cancer cells that have proven resistant to conventional pro-apoptotic treatments. Relatively little is known about the molecular basis of paraptosis, but perturbations of cellular proteostasis and ion homeostasis appear to critically contribute to the process. Ca2+ transport has been shown to be important in the paraptosis induced by several natural products, metal complexes, and co-treatment with proteasome inhibitors and certain Ca2+-modulating agents. In particular, the Ca2+-mediated communication between the ER and mitochondria plays a crucial role in paraptosis. Mitochondrial Ca2+ overload from the intracellular Ca2+-flux system located at the ER-mitochondrial axis can induce mitochondrial dilation during paraptosis, while the accumulation of misfolded proteins within the ER lumen is believed to exert an osmotic force and draw water from the cytoplasm to distend the ER lumen. In this process, Ca2+ release from the ER also critically contributes to aggravating ER stress and ER dilation. This review focuses on the role of Ca2+ transport in paraptosis by summarizing the recent findings related to the actions of Ca2+-modulating paraptosis-inducing agents and discussing the potential cancer therapeutic strategies that may effectively induce paraptosis via Ca2+ signaling.

The relationship between the pattern of shift work and sleep disturbances in Korean firefighters.

PURPOSE: Sleep disturbances are prevalent in firefighters, but the relationship between patterns of shift work and sleep disturbances has not yet been investigated. Here, this relationship has been evaluated in Korean firefighters. METHODS: A cross-sectional study was conducted using an online questionnaire, which captured demographic, psychosocial and work-related characteristics. Sleep disturbance was assessed using the insomnia severity index (ISI). The relationship between insomnia and work-related factors (including type of shift work and the frequency of emergency events and off-duty work which means overtime work on off days) was analyzed. RESULTS: A total of 9810 firefighters completed the survey, representing approximately 21.5% of all Korean firefighters; data from 9738 subjects were included in the analysis. All firefighter roles were significantly associated with insomnia; the odds ratio (OR) was 2.456 (95% confidence interval [CI] 1.461-4.128) for fire suppression and 1.871 (95% CI 1.105-3.167) for the emergency medical services and rescue. However, the pattern of shift work did not show a statistically significant relationship. The OR increased along with the frequency of emergency events and off-duty work (p value for trend < 0.05). CONCLUSIONS: This study found a significant association between the frequency of emergency and off-duty work and insomnia in Korean firefighters, whereas the pattern of shift work showed no significant relationship. Therefore, measures to reduce the frequency of emergency and off-duty work are required to prevent sleep disturbances in firefighters.

Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca2+ Overload.

The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, carfilzomib, and ixazomib, in many solid tumor cell lines by inducing paraptosis, which is accompanied by severe vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. We found that Ler potentiates Btz-mediated ER stress and ER dilation, possibly due to misfolded protein accumulation, in MDA-MB 435S cells. In addition, the combination of Btz and Ler triggers mitochondrial Ca2+ overload, critically contributing to mitochondrial dilation and subsequent paraptotic events, including mitochondrial membrane potential loss and ER dilation. Taken together, our results suggest that a combined regimen of PI and Ler may effectively kill cancer cells via structural and functional perturbations of the ER and mitochondria.