Comparison of Awake Respiratory Control Versus Sleep Obstructive Sleep Apnea Endotypes.

Most approaches to advance simplified physiology-based precision medicine strategies for obstructive sleep apnea (OSA) focus on sleep parameters (i.e., OSA endotypes). However, wakefulness physiology measures can also provide prediction insight for certain OSA therapies yet their relationship with sleep parameters has not been extensively investigated. This study aimed to investigate potential relationships between awake ventilatory control parameters and sleep OSA endotypes and their potential to predict changes in OSA severity with morphine. Data were acquired from a randomised, cross-over trial that investigated effects of morphine versus placebo on OSA severity and underlying mechanisms. Here, awake ventilatory chemoreflex testing prior to overnight polysomnography was compared with direct measures of sleep respiratory control (e.g., hypercapnic ventilatory responses and loop gain) and OSA endotypes during a separate overnight physiology study (pharyngeal critical closure pressure-Pcrit, muscle responsiveness via genioglossus intramuscular electromyography and arousal threshold via epiglottic pressure catheter to transient continuous positive airway pressure reductions). Twenty-one men with OSA completed both study arms. During placebo, 1) awake chemosensitivity correlated with Pcrit (r=0.726, p=0.001), 2) arousal threshold correlated with awake CO2 ventilatory response threshold (r=-0.467, p=0.047) and basal ventilation (r=-0.500, p=0.029). Awake chemosensitivity and Pcrit also correlated with the apnea-hypopnea index (p<0.001) during placebo. Awake chemosensitivity was predictive of changes in OSA severity with morphine(r=-0.535, p=0.013). In conclusion, awake measures of respiratory control are related to physiological endotypes such as airway collapsibility and arousal threshold during sleep and OSA severity. Awake ventilatory chemosensitivity has the best potential to predict changes in OSA severity with morphine.

In vitro models to evaluate multidrug resistance in cancer cells: Biochemical and morphological techniques and pharmacological strategies.

The overexpression of ATP-binding cassette (ABC) transporters contributes to the failure of chemotherapies and symbolizes a great challenge in oncology, associated with the adaptation of tumor cells to anticancer drugs such that these transporters become less effective, a mechanism known as multidrug resistance (MDR). The aim of this review is to present the most widely used methodologies for induction and comprehension of in vitro models for detection of multidrug-resistant (MDR) modulators or inhibitors, including biochemical and morphological techniques for chemosensitivity studies. The overexpression of MDR proteins, predominantly, the subfamily glycoprotein-1 (P-gp or ABCB1) multidrug resistance, multidrug resistance-associated protein 1 (MRP1 or ABCCC1), multidrug resistance-associated protein 2 (MRP2 or ABCC2) and cancer resistance protein (ABCG2), in chemotherapy-exposed cancer lines have been established/investigated by several techniques. Amongst these techniques, the most used are (i) colorimetric/fluorescent indirect bioassays, (ii) rhodamine and efflux analysis, (iii) release of 3,30-diethyloxacarbocyanine iodide by fluorescence microscopy and flow cytometry to measure P-gp function and other ABC transporters, (iv) exclusion of calcein-acetoxymethylester, (v) ATPase assays to distinguish types of interaction with ABC transporters, (vi) morphology to detail phenotypic characteristics in transformed cells, (vii) molecular testing of resistance-related proteins (RT-qPCR) and (viii) 2D and 3D models, (ix) organoids, and (x) microfluidic technology. Then, in vitro models for detecting chemotherapy MDR cells to assess innovative therapies to modulate or inhibit tumor cell growth and overcome clinical resistance. It is noteworthy that different therapies including anti-miRNAs, antibody-drug conjugates (to natural products), and epigenetic modifications were also considered as promising alternatives, since currently no anti-MDR therapies are able to improve patient quality of life. Therefore, there is also urgency for new clinical markers of resistance to more reliably reflect in vivo effectiveness of novel antitumor drugs.

miRNA-driven sensitization of breast cancer cells to Doxorubicin treatment following exposure to low dose of Zinc Oxide nanoparticles.

The impact of Engineered nanomaterials (ENMs) (i.e., Zinc Oxide nanoparticles (ZnO NPs)) on human health has been investigated at high and unrealistic exposure levels, overlooking the potential indirect harm of subtoxic and long exposures. Therefore, this study aimed to investigate the impacts of subtoxic concentrations of zinc oxide (ZnO NPs) on breast cancer cells' response to Doxorubicin. Zinc oxide nanoparticles caused a concentration-dependent reduction of cell viability in multiple breast cancer cell lines. A subtoxic concentration of 1.56 µg/mL (i.e., no observed adverse effect level) was used in subsequent mechanistic studies. Molecularly, miRNA profiling revealed significant downregulation of 13 oncogenic miRNAs (OncomiRs) in cells exposed to the sub-toxic dose of ZnO NPs followed by doxorubicin treatment. Our comprehensive bioinformatic analysis has identified 617 target genes enriched in ten pathways, mainly regulating gene expression and transcription, cell cycle, and apoptotic cell death. Several tumor suppressor genes emerged as validated direct targets of the 13 OncomiRs, including TFDP2, YWHAG, SMAD2, SMAD4, CDKN1A, CDKN1B, BCL2L11, and TGIF2. This study insinuates the importance of miRNAs in regulating the responsiveness of cancer cells to chemotherapy. Our findings further indicate that being exposed to environmental ENMs, even at levels below toxicity, might still modulate cancer cells' response to chemotherapy, which highlights the need to reestablish endpoints of ENM exposure and toxicity in cancer patients receiving chemotherapeutics.

Impact of Tumoral ß2-Adrenergic Receptor Expression on Chemotherapeutic Response and Prognosis in Patients with Advanced Colorectal Cancer.

BACKGROUND: The ß2-adrenergic receptor (ß2-AR) is a therapeutic target for circulatory agonists and exhibits oncogenic activity in several cancers. However, its role in advanced colorectal cancer (CRC) treated using chemotherapy remains unclear. We investigated the potential of ß2-AR as a novel chemosensitivity marker and therapeutic target in inoperable CRC. METHODS: ß2-AR expression was evaluated immunohistochemically in 80 advanced or recurrent CRC cases for which untreated resected specimens were available before systemic chemotherapy implementation. We assessed the relationship among ß2-AR protein expression, clinicopathological factors, therapeutic response, and prognosis. Furthermore, we evaluated the significance of ß2-AR as an in vitro and in vivo therapeutic target using CRC cell lines and a CRC xenograft model treated with the ß-blocker, propranolol, and other anticancer agents. RESULTS: High tumoral ß2-AR expression was associated with shorter progression-free survival and chemotherapeutic resistance in patients treated with oxaliplatin-based regimens and bevacizumab-based regimens. We found no synergistic effect between propranolol and oxaliplatin. However, combined administration of propranolol and bevacizumab induced significant tumor shrinkage in the CRC xenograft model. CONCLUSIONS: ß2-AR is a possible biomarker for chemosensitivity and prognosis in advanced CRC. Repositioning existing ß-blockers could be beneficial for treating CRC resistant to existing treatment regimens.

Fascin Inhibitor NP-G2-044 Decreases Cell Metastasis and Increases Overall Survival of Mice-Bearing Lung Cancers.

AIM: Fascin is an actin-binding protein that promotes tumor metastasis. The inhibition of fascin on the progress of non-small cell lung cancer (NSCLC) is not very clear. Hence, this study explored the potential effect of NP-G2-044, a novel fascin inhibitor, in human NSCLC lines and the Lewis lung cancer (LCC) mice model. METHODS: The growth of cells was analyzed via CCK-8 assays, and the flow cytometry was adopted for cell cycle and apoptosis analysis, as well as the migration and invasion of NSCLC cells with or without NP-G2-044. The therapy of NP-G2-044, which synergizes with cisplatin and PD-1, was evaluated in the established xenograft Lewis's lung cancer of mice. RESULTS: Fascin was overexpressed in human NSCLC cells, and inhibition of fascin by NP-G2-044 attenuated NSCLC cell growth and remarkably undermined the ability of migration and invasion in vitro, which was related to the reduced epithelialmesenchymal transition (EMT) including downregulation of N-cadherin and vimentin, and upregulation of E-cadherin. Further results implied that the above changes may be partially mediated by the Wnt/ß-catenin pathway. In vivo, NP-G2-044 slowed down tumor development and enhanced overall survival alone, leading to synergistic anticancer effects with cisplatin or PD-1 inhibitor. CONCLUSION: Fascin inhibition could inhibit the metastasis of NSCLC and has the potential to enhance the efficacy of cisplatin and PD-1 inhibitors by blocking the Wnt/ß- catenin pathway.

Development of transcriptomic tools for predicting the response to individual drug of the mFOLFIRINOX regimen in patients with metastatic pancreatic cancer.

Background: The utilization of modified FOLFIRINOX (mFFX) therapy has shown notable advancements in patient outcomes in both localized and metastatic PDAC. Nevertheless, the effectiveness of mFFX treatment comes at the cost of elevated toxicity, leading to its restriction to patients with adequate performance status. Consequently, the administration of mFFX is contingent upon patient performance rather than rational criteria. The ideal scenario would involve the ability to assess the sensitivity of each drug within the mFFX regimen, minimizing unnecessary toxicity without compromising clinical benefits. Methods: We developed transcriptomic signatures for each drug of the mFFX regimen (5FU, oxaliplatin and irinotecan) by integrating transcriptomic data from PDC, PDO and PDX with their corresponding chemo-response profiles to capture the biological components responsible for the response to each drug. We further validated the signatures in a cohort of 167 patients with advanced and metastatic PDAC. Results: All three signatures captured high responder patients for OS and PFS in the mFFX arm exclusively. We then studied the response of patients to 0, 1, 2 and 3 drugs and we identified a positive correlation between the number of drugs predicted as sensitive and the OS and PFS, and the with objective response rate. Conclusions: We developed three novel transcriptome-based signatures which define sensitivity for each mFFX components that can be used to rationalize the administration of the mFFX regimen in patients with metastatic pancreatic cancer and could help to avoid unnecessary toxic effects.

PGK1 can affect the prognosis and development of bladder cancer.

BACKGROUND: Previous studies have demonstrated that the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) can promote tumor development. This study sought to investigate the specific role of PGK1 in bladder cancer (BLCA). METHODS: Public databases and immunohistochemistry assays were utilized to analyze the expression of PGK1 in BLCA and its prognostic significance. Cell proliferation was assessed through CCK-8 and colony formation assays, while the level of metastasis was evaluated using transwell migration experiments. Additionally, IC50 experiments were conducted to assess the impact of PGK1 on cisplatin sensitivity. RESULTS: The mRNA and protein expression levels of PGK1 were significantly upregulated in BLCA. Cox proportional hazards model analysis revealed that PGK1 and T stage were independent prognostic factors for BLCA patients. Both CCK-8 and colony assays demonstrated that PGK1 promotes proliferation. Furthermore, a positive correlation was observed between PGK1 and Ki67, a proliferation index. Transwell migration assays confirmed the ability of PGK1 to enhance metastasis. Finally, PGK1 increased the IC50 associated with cisplatin treatment in BLCA. CONCLUSION: Collectively, these findings suggest that PGK1 may hold clinical value in predicting BLCA prognosis and improving the outcomes of this patient population.

The METTL3/TRAP1 axis as a key regulator of 5-fluorouracil chemosensitivity in colorectal cancer.

Colorectal cancer (CRC) remains a significant clinical challenge, with 5-Fluorouracil (5-FU) being the frontline chemotherapy. However, chemoresistance remains a major obstacle to effective treatment. METTL3, a key methyltransferase involved in RNA methylation processes, has been implicated in CRC carcinogenesis. However, its role in modulating CRC sensitivity to 5-FU remains elusive. In this study, we aimed to investigate the role and mechanisms of METTL3 in regulating 5-FU chemosensitivity in CRC cells. Initially, we observed that 5-FU treatment inhibited cell viability and induced apoptosis, accompanied by a reduction in METTL3 expression in HCT-116 and HCT-8 cells. Subsequent assays including drug sensitivity, EdU, colony formation, TUNEL staining, and flow cytometry revealed that METTL3 depletion enhanced 5-FU sensitivity and increased apoptosis induction both in vitro and in vivo. Conversely, METTL3 overexpression conferred resistance to 5-FU in both cell lines. Moreover, knockdown of METTL3 in 5-FU-resistant CRC cell lines HCT-116/FU and HCT-15/FU significantly decreased 5-FU tolerance and induced apoptosis upon 5-FU treatment. Mechanistically, we found that METTL3 regulated 5-FU sensitivity and apoptosis induction by modulating TRAP1 expression. Further investigations using m6A colorimetric ELISA, dot blot, MeRIP-qPCR and RNA stability assays demonstrated that METTL3 regulated TRAP1 mRNA stability in an m6A-dependent manner. Additionally, overexpression of TRAP1 mitigated the cytotoxic effects of 5-FU on CRC cells. In summary, our study uncovers the pivotal role of the METTL3/TRAP1 axis in modulating 5-FU chemosensitivity in CRC. These findings provide new insights into the mechanisms underlying CRC resistance to 5-FU and may offer potential targets for future therapeutic interventions.

WTAP weakens oxaliplatin chemosensitivity of colorectal cancer by preventing PANoptosis.

As the most abundant post-transcriptional modification in eukaryotes, N6-methyladenosine (m6A) plays a crucial role in cancer cell proliferation, invasion and chemoresistance. However, its specific effects on chemosensitivity to oxaliplatin-based regimens and the impact of these drugs on m6A methylation levels in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrated that the m6A methyltransferase Wilms tumor 1-associating protein (WTAP) weakens oxaliplatin chemosensitivity in HCT116 and DLD1 cells. Mechanistically, oxaliplatin treatment upregulated WTAP expression, preventing multiple forms of cell death simultaneously, a process known as PANoptosis, by decreasing intracellular oxidative stress through maintaining the expression of nuclear factor erythroid-2-related factor 2 (NRF2), a major antioxidant response element, in an m6A-dependent manner. In addition, high WTAP expression in CRC patients is associated with a poor prognosis and reduced benefit from standard chemotherapy by clinical data analysis of The Cancer Genome Atlas (TCGA) database and patient cohort study. These findings suggest that targeting WTAP-NRF2-PANoptosis axis could enhance the antitumor efficacy of oxaliplatin-based chemotherapy in CRC treatment.

Reversible chemoresistance of pancreatic cancer grown as spheroids.

Better in vitro models are needed to identify active drugs to treat pancreatic adenocarcinoma (PAC) patients. We used 3D hanging drop cultures to produce spheroids from five PAC cell lines and tested nine FDA-approved drugs in clinical use. All PAC cell lines in 2D culture were sensitive to three drugs (gemcitabine, docetaxel and nab-paclitaxel), however most PAC (4/5) 3D spheroids acquired profound chemoresistance even at 10 µM. In contrast, spheroids retained sensitivity to the investigational drug triptolide, which induced apoptosis. The acquired chemoresistance was also transiently retained when cells were placed back into 2D culture and six genes potentially associated with chemoresistance were identified by microarray and confirmed using quantitative RT-PCR. We demonstrate the additive effect of gemcitabine and erlotinib, from the 12 different combinations of nine drugs tested. This comprehensive study shows spheroids as a useful multicellular model of PAC for drug screening and elucidating the mechanism of chemoresistance.

Chemotactic signaling pathways in prostate cancer: Implications in the tumor microenvironment and as potential therapeutic targets.

Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.

CDC20 Holds Novel Regulation Mechanism in RPA1 during Different Stages of DNA Damage to Induce Radio-Chemoresistance.

Targeting CDC20 can enhance the radiosensitivity of tumor cells, but the function and mechanism of CDC20 on DNA damage repair response remains vague. To examine that issue, tumor cell lines, including KYSE200, KYSE450, and HCT116, were utilized to detect the expression, function, and underlying mechanism of CDC20 in radio-chemoresistance. Western blot and immunofluorescence staining were employed to confirm CDC20 expression and location, and radiation could upregulate the expression of CDC20 in the cell nucleus. The homologous recombination (HR) and non-homologous end joining (NHEJ) reporter gene systems were utilized to explore the impact of CDC20 on DNA damage repair, indicating that CDC20 could promote HR repair and radio/chemo-resistance. In the early stages of DNA damage, CDC20 stabilizes the RPA1 protein through protein-protein interactions, activating the ATR-mediated signaling cascade, thereby aiding in genomic repair. In the later stages, CDC20 assists in the subsequent steps of damage repair by the ubiquitin-mediated degradation of RPA1. CCK-8 and colony formation assay were used to detect the function of CDC20 in cell vitality and proliferation, and targeting CDC20 can exacerbate the increase in DNA damage levels caused by cisplatin or etoposide. A tumor xenograft model was conducted in BALB/c-nu/nu mice to confirm the function of CDC20 in vivo, confirming the in vitro results. In conclusion, this study provides further validation of the potential clinical significance of CDC20 as a strategy to overcome radio-chemoresistance via uncovering a novel role of CDC20 in regulating RPA1 during DNA damage repair.

Central and peripheral mechanisms underlying respiratory deficits in a mouse model of accelerated senescence.

Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10 months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10 min) or hypercapnia (FiCO2 = 0.07; 10 min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10 months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model.

MAPK Signaling-Mediated RFNG Phosphorylation and Nuclear Translocation Restrain Oxaliplatin-Induced Apoptosis and Ferroptosis.

Chemotherapy resistance remains a major challenge in the treatment of colorectal cancer (CRC). Therefore, it is crucial to develop novel strategies to sensitize cancer cells to chemotherapy. Here, the fringe family is screened to determine their contribution to chemotherapy resistance in CRC. It is found that RFNG depletion significantly sensitizes cancer cells to oxaliplatin treatment. Mechanistically, chemotherapy-activated MAPK signaling induces ERK to phosphorylate RFNG Ser255 residue. Phosphorylated RFNG S255 (pS255) interacts with the nuclear importin proteins KPNA1/importin-α1 and KPNB1/importin-ß1, leading to its translocation into the nucleus where it targets p53 and inhibits its phosphorylation by competitively inhibiting the binding of CHK2 to p53. Consequently, the expression of CDKN1A is decreased and that of SLC7A11 is increased, leading to the inhibition of apoptosis and ferroptosis. In contrast, phosphor-deficient RFNG S225A mutant showed increased apoptosis and ferroptosis, and exhibited a notable response to oxaliplatin chemotherapy both in vitro and in vivo. It is further revealed that patients with low RFNG pS255 exhibited significant sensitivity to oxaliplatin in a patient-derived xenograft (PDX) model. These findings highlight the crosstalk between the MAPK and p53 signaling pathways through RFNG, which mediates oxaliplatin resistance in CRC. Additionally, this study provides guidance for oxaliplatin treatment of CRC patients.

Iron Overloading Potentiates the Antitumor Activity of 5-Fluorouracil by Promoting Apoptosis and Ferroptosis in Colorectal Cancer Cells.

Resistance to 5-fluorouracil (5-FU) remains a significant challenge in colorectal cancer (CRC) treatment. Ferric ammonium citrate (FAC) is commonly used as an iron supplement due to its food-fortification properties; however, its potential role as a chemosensitizer in cancer therapy has not been studied. In this study, we explored the ability of FAC to sensitize CRC cells and increase their susceptibility to 5-FU-mediated anticancer effects. We assessed cell viability, cell cycle progression, apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, ferroptosis, and iron metabolism-related protein expression using two CRC cell lines. Additionally, we conducted in silico analyses to compare iron markers in normal colon and CRC tumor tissues. Compared to controls, CRC cells pretreated with FAC and then treated with 5-FU exhibited significantly reduced growth and viability, along with increased ROS-mediated ferroptosis. Mechanistically, FAC-pretreated then 5-FU-treated CRC cells showed enhanced apoptosis, increased Bak/Bax expression, MMP depolarization, and decreased antiapoptotic protein levels (Bcl-2 and Bcl-xL). This combined treatment also led to G2/M cell cycle arrest, upregulation of p21 and p27, and downregulation of cyclin D1, c-Myc, survivin, and GPX4. Analysis of human colon tumor tissue revealed decreased expression of IRP-1, HMOX-1, and FTH1 but increased HAMP expression. In contrast, FAC-pretreated/5-FU-treated CRC cells exhibited a reverse pattern, suggesting that FAC-induced chemosensitization enhances 5-FU-mediated anticancer activity in CRC by disrupting iron homeostasis. These findings highlight the potential of iron overload as a chemosensitization strategy for improving CRC chemotherapy.

A Pyroptosis-Related Gene Signature Predicts Prognosis and Tumor Immune Microenvironment in Colorectal Cancer.

Pyroptosis is a programmed cell death, which garners increasing attention by relating to immune and therapy response. However, the role of pyroptosis in colorectal cancer (CRC) remains unclear. Our study mainly to explore the role of pyroptosis in CRC. The mRNA expression data and corresponding clinical information of CRC patients were achieved from The Cancer Genome Atlas (TCGA). Pyroptosis-related genes (PRGs) were identified using DESeq2 R package and biological function was analyzed using cluster Profiler R package. A PRGs-based prognosis model was constructed by a univariate Cox and LASSO regression analyses. Then, the affecting of risk signature to clinicopathological characteristics, immune status and infiltrated immune cells, immune checkpoint and chemotherapy sensitivity was analyzed. qRT-PCR and IHC were performed for the expression level of PRGs. Moreover, a nomogram predict model was constructed. Total 57 PRGs were identified between 500 CRC samples and 44 normal samples. Those PRGs mainly enriched in immune-related and pyroptosis-related pathways. GABRD, NADK, TMEM240, RER1, AGRN, UBE2J2, CALML6, PLCH2, TMEM88B have been identified as gene signature and a prognostic model was constructed and validated. CRC patients with high-risk score showed poor survival, high TMB score, high proportion of CD4 + memory T cells, common lymphoid progenitors, cancer associated fibroblasts, mast cells, and neutrophils. The immune checkpoint related genes, CD160, CD200R1, CD244, CD28, CD40LG, CD44, CD48, CD80, CD86, HHLA2, ICOS, IDO1, TIGIT, TNFRSF25, TNFRSF4, TNFRSF9, TNFSF15, TNFSF18 also increased in high-risk score group. CRC patients with high-risk score more sensitive to docetaxel and rapamycin but resistance to gemcitabine and mitomycin. Moreover, a predictive nomogram for 1-, 3-, 5-year for CRC patients was established and validated. In the study, a PRGs-based prognostic model and a predictive model were constructed. These models are effective and robust in prediction the 1-, 3-, and 5-year survival of CRC patients.

Chromosome instability functions as a potential therapeutic reference by enhancing chemosensitivity to BCL-XL inhibitors in colorectal carcinoma.

Chromosome instability (CIN) and subsequent aneuploidy are prevalent in various human malignancies, influencing tumor progression such as metastases and relapses. Extensive studies demonstrate the development of chemoresistance in high-CIN tumors, which poses significant therapeutic challenges. Given the association of CIN with poorer prognosis and suppressed immune microenvironment observed in colorectal carcinoma (CRC), here we aimed to discover chemotherapeutic drugs exhibiting increased inhibition against high-CIN CRC cells. By using machine learning methods, we screened out two BCL-XL inhibitors Navitoclax and WEHI-539 as CIN-sensitive reagents in CRC. Subsequent analyses using a CIN-aneuploidy cell model confirmed the vulnerability of high-CIN CRC cells to these drugs. We further revealed the critical role of BCL-XL in the viability of high-CIN CRC cells. In addition, to ease the evaluation of CIN levels in clinic, we developed a three-gene signature as a CIN surrogate to predict prognosis, chemotherapeutic and immune responses in CRC samples. Our results demonstrate the potential value of CIN as a therapeutic target in CRC treatment and the importance of BCL-XL in regulating survival of high-CIN CRC cells, therefore representing a valuable attempt to translate a common trait of heterogeneous tumor cells into an effective therapeutic target.

TRIM47 inhibits cisplatin chemosensitivity and endoplasmic reticulum stress-induced apoptosis of ovarian cancer cells.

Ovarian cancer (OC) is the fifth most common cause of death in women worldwide. Chemoresistance is a key reason for treatment failure, causing high mortality. As a member of the tripartite motif-containing (TRIM) protein family, tripartite motif 47 (TRIM47) plays a vital role in the carcinogenesis and drug resistance of various cancers. This study investigated the impact and mechanisms of TRIM47 on cisplatin (DDP) chemosensitivity and apoptosis in OC. OC cell viability was assessed with a cell counting kit-8 assay and OC cell apoptosis was assessed using flow cytometry, caspase-3 and caspase-9 activity, and Bax and Bcl-2 expression assays while gene and protein expression were assessed using qRT-PCR and Western blot assays. The expression of TRIM47 was significantly increased in both DDP-resistant tissues from patients with OC tissues and in cancer cell lines compared with that in normal tissue or parental cell lines. The increased level of TRIM47 correlated with poor prognosis in patients with OC. Functional assays demonstrated that TRIM47 promoted DDP resistance both in vitro and in vivo. The increased viability and reduced apoptosis of OC cells induced by TRIM47 can be rescued by the endoplasmic reticulum (ER) stress-inducer tunicamycin, suggesting that TRIM47 inhibits OC cell apoptosis by suppressing ER stress. Therefore, TRIM47 may be targeted as a therapeutic strategy for DDP resistance in OC.

Tanshinone I improves TNBC chemosensitivity by suppressing late-phase autophagy through AKT/p38 MAPK signaling pathway.

The inhibition of autophagy is a potential therapeutic strategy to improve the chemosensitivity of triple-negative breast cancer (TNBC). In this study, we demonstrated that a natural terpenoid tanshinone I (TAN) enhanced the effectiveness of paclitaxel (PTX), at least in part, through an autophagy-dependent mechanism against TNBC. In vitro validation demonstrated that the combined therapy resulted in a synergistic decrease in the growth of TNBC cells. The chemosensitizing impact of TAN might be attributed to its inhibition of PTX-induced autophagy in the late phase by obstructing the fusion of autophagosomes and lysosomes, rather than by inhibiting lysosomal function. The findings from KEGG pathway analysis and molecular docking suggested that TAN might impact breast cancer chemoresistance primarily through the PI3K-Akt and MAPK signaling pathways. The non-canonical AKT/p38 MAPK signaling was further validated as the primary mechanism responsible for the inhibition of autophagy by TAN. In vivo study showed that the combined administration of TAN and PTX demonstrated a more significant suppression of tumor growth and autophagic activity compared to PTX monotherapy in the MDA-MB-231 xenograft nude mouse model. The safety evaluation of TAN in a zebrafish model, along with in vitro and in vivo validation, provided experimental and pre-clinical data supporting its potential as a natural adjunctive therapy in TNBC. Overall, this study suggests that the combination of TAN with PTX could provide an effective treatment option for advanced breast cancer, and targeting the AKT/p38 MAPK/late-autophagy signaling axis may be a promising approach for developing therapeutic interventions against TNBC.