The Role of Plasma Membrane Viscosity in the Response and Resistance of Cancer Cells to Oxaliplatin.
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ABSTRACT:
SUBMITTER: Shimolina L
PROVIDER: S-EPMC8699340 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.
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Project description:BackgroundGastric carcinoma (GC) is one of the most deadly diseases due to tumour metastasis and resistance to therapy. Understanding the molecular mechanism of tumour progression and drug resistance will improve therapeutic efficacy and develop novel intervention strategies.MethodsDifferentially expressed long non-coding RNAs (lncRNAs) in clinical specimens were identified by LncRNA microarrays and validated in different clinical cohorts by quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation and bioinformatics analysis. Biological functions of lncRNA were investigated by using cell proliferation assays, migration assays, xenograft tumour models and bioinformatics analysis. Effects of lncSLCO1C1 on GC cell survival were assessed by comet assays and immunofluorescence assays. Underlying molecular mechanisms were further explored by using a number of technologies including RNA pull-down, mass spectrometry analysis, RNA immunoprecipitation, co-immunoprecipitation, miRNA sequencing, luciferase reporter assays and molecular modelling.ResultsLncSLCO1C1 was highly upregulated in GC tissue samples and associated with GC patients' poor overall survival. Overexpression of lncSLCO1C1 promoted proliferation and migration, whereas decreased lncSLCO1C1 expression produced the opposite effects. lncSLCO1C1 also mediated tumour resistance to chemotherapy with oxaliplatin by reducing DNA damage and increasing cell proliferation. Despite sequence overlapping between lncSLCO1C1 and PDE3A, alternations of PDE3A expression had no effect on the GC cell progression, indicating that lncSLCO1C1, not PDE3A, related with the progression of GC cells. Mechanistically, lncSLCO1C1 serves as a scaffold for the structure-specific recognition protein 1 (SSRP1)/H2A/H2B complex and regulates the function of SSRP1 in reducing DNA damage. Meanwhile, lncSLCO1C1 functions as a sponge to adsorb miR-204-5p and miR-211-5p that target SSRP1 mRNA, and thus increases SSRP1 expression. Patients with high expressions of both lncSLCO1C1 and SSRP1 have poor overall survival, highlighting the role of lncSLCO1C1 in GC progression.ConclusionsLncSLCO1C1 promotes GC progression by enhancing cell growth and preventing DNA damage via interacting and scaffolding the SSRP1/H2A/H2b complex and absorbing both miR-211-5p and miR-204-5p to increase SSRP1 expression.
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Project description:There is growing evidence to support a role for the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in resistance to a variety of chemotherapeutic agents. Whether GCS contributes to oxaliplatin resistance in colorectal cancer (CRC) has not yet been determined. We have addressed this potentially important clinical issue by examining GCS function in two panels of oxaliplatin-resistant, isogenic CRC cell lines. Compared to parental cell lines, oxaliplatin-resistant cells have increased expression of GCS protein associated with increased levels of the pro-survival ceramide metabolite, glucosylceramide (GlcCer). Inhibition of GCS expression by RNAi-mediated gene knockdown resulted in a reduction in cellular GlcCer levels, with restored sensitivity to oxaliplatin. Furthermore, oxaliplatin-resistant CRC cells displayed lower ceramide levels both basally and after treatment with oxaliplatin, compared to parental cells. GlcCer, formed by GCS-mediated ceramide glycosylation, is the precursor to a complex array of glycosphingolipids. Differences in cellular levels and species of gangliosides, a family of glycosphingolipids, were also seen between parental and oxaliplatin-resistant CRC cells. Increased Akt activation was also observed in oxaliplatin-resistant CRC cell lines, together with increased expression of the anti-apoptotic protein survivin. Finally, this study shows that GCS protein levels are greatly increased in human CRC specimens, compared to matched, normal colonic mucosa, and that high levels of UGCG gene expression are significantly associated with decreased disease-free survival in colorectal cancer patients. These findings uncover an important cellular role for GCS in oxaliplatin chemosensitivity and may provide a novel cellular target for augmenting chemotherapeutic drug effectiveness in CRC.
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Project description:The viscosity is a highly important parameter within the cell membrane, affecting the diffusion of small molecules and, hence, controlling the rates of intracellular reactions. There is significant interest in the direct, quantitative assessment of membrane viscosity. Here we report the use of fluorescence lifetime imaging microscopy of the molecular rotor BODIPY C10 in the membranes of live Escherichia coli bacteria to permit direct quantification of the viscosity. Using this approach, we investigated the viscosity in live E. coli cells, spheroplasts, and liposomes made from E. coli membrane extracts. For live cells and spheroplasts, the viscosity was measured at both room temperature (23°C) and the E. coli growth temperature (37°C), while the membrane extract liposomes were studied over a range of measurement temperatures (5-40°C). At 37°C, we recorded a membrane viscosity in live E. coli cells of 950 cP, which is considerably higher than that previously observed in other live cell membranes (e.g., eukaryotic cells, membranes of Bacillus vegetative cells). Interestingly, this indicates that E. coli cells exhibit a high degree of lipid ordering within their liquid-phase plasma membranes.
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Project description:Colorectal cancer (CRC), a commonly occurring malignant tumor in the gastrointestinal tract, is the third leading cause of cancer‑related deaths worldwide. FK506‑binding proteins (FKBPs) comprise an immunophilin family that are involved in the carcinogenesis, progression and chemoresistance of cancers, including CRC. FKBP3 (also known as FKBP25) is a nuclear protein that is a member of the FKBP family and is correlated with the activity of histone deacetylase 2 (HDAC2). However, the role of FKBP3 and HDAC2 in oxaliplatin resistance in CRC and the potential molecular mechanisms are still poorly understood. In the present study, the expression of FKBP3, HDAC2 and related‑genes was detected by real‑time PCR and western blot analysis. Furthermore, cell apoptosis was detected by flow cytometry (FCM). We found high expression of FKBP3 and HDAC2 in CRC tissues. In vitro, primary CRC cells with high expression of FKBP3 and HDAC2 were insensitive to oxaliplatin. Downregulation of FKBP3 significantly increased the sensitivity of primary CRC cells to oxaliplatin, reduced expression of HDAC2, permeability glycoprotein (P‑gp) and phosphorylated AKT (p‑AKT), and increased expression of phosphatase and tensin homolog (PTEN) and cleaved caspase‑3. Accordingly, upregulation of FKBP3 had the opposite effect. Furthermore, downregulation of HDAC2 significantly counteracted FKBP3‑induced oxaliplatin resistance in CRC cells. Our data revealed that oxaliplatin resistance in CRC cells is positively associated with FKBP3 and HDAC2 expression, and FKBP3 downregulation could attenuate oxaliplatin resistance in CRC cells by reducing HDAC2 expression and possibly through regulation of the PTEN/AKT pathway.
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Project description:Human WBSCR22 gene is involved in tumor metastasis, cell growth and invasion, however, its role in chemosensitivity to antitumor agents remains unknown. In this study, we analyzed the TCGA cohort and found the expression of WBSCR22 was significantly elevated in human colorectal cancer (CRC) tissue. WBSCR22 could be served as an independent risk predictor for overall survival (OS), and up-regulated WBSCR22 could predict unfavorable OS for CRC patients. Knockdown of WBSCR22 significantly sensitized CRC cells to oxaliplatin in vitro and in vivo, while overexpression of WBSCR22 led to cellular resistance to oxaliplatin treatment. Although WBSCR22 knockdown did not change cell cycle, it increased the oxaliplatin-induced cellular apoptosis. WBSCR22 knockdown augmented the oxaliplatin-induced intracellular reactive oxygen species (ROS) production and ROS-induced 8-oxoguanine (8-oxoG) oxidative lesion accumulation, likely sensitizing oxaliplatin treatment. These results demonstrate that WBSCR22 is involved in CRC resistance to oxaliplatin, suggesting WBSCR22 may represent a novel oxaliplatin resistance biomarker as well as a potentail target for CRC therapeutics.
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Project description:Regulation of plasma membrane curvature and composition governs essential cellular processes. The material property of bending rigidity describes the energetic cost of membrane deformations and depends on the plasma membrane molecular composition. Because of compositional fluctuations and active processes, it is challenging to measure it in intact cells. Here, we study the plasma membrane using giant plasma membrane vesicles (GPMVs), which largely preserve the plasma membrane lipidome and proteome. We show that the bending rigidity of plasma membranes under varied conditions is correlated to readout from environment-sensitive dyes, which are indicative of membrane order and microviscosity. This correlation holds across different cell lines, upon cholesterol depletion or enrichment of the plasma membrane, and variations in cell density. Thus, polarity- and viscosity-sensitive probes represent a promising indicator of membrane mechanical properties. Additionally, our results allow for identifying synthetic membranes with a few well defined lipids as optimal plasma membrane mimetics.
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Project description:The efficacy of chemotherapy for colon cancer is limited due to the development of chemoresistance. MicroRNA (miR)-188-5p is downregulated in various types of cancer. The aim of the present study was to explore the molecular role of miR-188 in oxaliplatin (OXA) resistance. An OXA-resistant colon cancer cell line, SW480/OXA, was used to examine the effects of miR-188-5p on the sensitivity of colon cancer cells to OXA. The target of miR-188-5p was identified using a luciferase assay. Cell cycle distribution was also assessed using flow cytometry. The measurement of p21 protein expression, Hoechst 33342 staining and Annexin V/propidium iodide staining was used to evaluate apoptosis. The expression of miR-188-5p significantly increased in SW480/OXA compared with wild-type SW480 cells. The luciferase assay demonstrated that miR-188-5p inhibited Ras GTPase-activating protein 1 (RASA1; also known as p120/RasGAP) luciferase activity by binding to the 3'-untranslated region of RASA1 mRNA, suggesting that miR-188-5p could target RASA1. In addition, miR-188-5p downregulation or RASA1 overexpression promoted the chemosensitivity of SW480/OXA, as evidenced by increased apoptosis and G1/S cell cycle arrest. Moreover, RASA1 silencing abrogated the increase in cell apoptosis induced by the miR-188-5p inhibitor. The findings of the present study suggested that miR-188-5p could enhance colon cancer cell chemosensitivity by promoting the expression of RASA1.
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Project description:Oxaliplatin resistance is a major challenge in the treatment of colorectal cancer (CRC). Many molecular targeted drugs for refractory CRC have been developed to solve CRC drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin resistance remain unclear. Here, we successfully constructed CRC PDOs and selected the Kruppel-like factor 5 (KLF5) inhibitor ML264 as the research object based on the results of the in vitro drug screening assay. ML264 significantly restored oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signaling pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcame oxaliplatin resistance in xenograft tumors. Taken together, our study demonstrated that ML264 can restore oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 may be a potential therapeutic target for oxaliplatin-resistant CRC. PDOs have a strong potential for evaluating inhibitors and drug combination therapy in a preclinical environment.
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Project description:In this report, we showed that two tumor cell characteristics, namely the malignancy and drug-resistance status can be evaluated by their membrane resealing response. Specifically, membrane pores in a number of pairs of cancer and normal cell lines originated from nasopharynx, lung and intestine were introduced by nano-mechanical puncturing. Interestingly, such nanometer-sized holes in tumor cells can reseal ~2-3 times faster than those in the corresponding normal cells. Furthermore, the membrane resealing time in cancer cell lines exhibiting resistance to several leading chemotherapeutic drugs was also found to be substantially shorter than that in their drug-sensitive counterparts, demonstrating the potential of using this quantity as a novel marker for future cancer diagnosis and drug resistance detection. Finally, a simple model was proposed to explain the observed resealing dynamics of cells which suggested that the distinct response exhibited by normal, tumor and drug resistant cells is likely due to the different tension levels in their lipid membranes, a conclusion that is also supported by direct cortical tension measurement.
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