Dataset Information

Multi-Omics Analysis Revealed Significant Metabolic Changes in Brain Cancer Cells Treated with Paclitaxel and/or Topotecan

ABSTRACT: Glioblastoma (GB) is the most common primary malignant brain tumor, representing approximately 57% of all gliomas and 48% of all primary malignant central nervous system (CNS) tumors. Despite the best standard therapies, glioblastoma survivors have a brief survival time, about 24 months on average. The treatment is troublesome because the cancer cells may not respond well to specific therapies as they grow within an extensive network of blood vessels. A multi-omics approach to provide information on biomolecules from multiple layers appears promising for systematically and holistically understanding complex biology. However, till now, only few studies have utilized omics analysis to investigate the impact of anticancer drugs on GBM. Our study aimed to evaluate the impacts of the anticancer medications (paclitaxel 5.3 μg/mL and topotecan 0.26 μM) solely and in pairwise combination on the metabolic and proteomic signatures of the U87 cell line while utilizing the accurate ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) analytical technology. The studied cancer cells wear treated with DMSO (control group), paclitaxel 5.3 µM, topotecan 0.26 µM, and a combination of paclitaxel 5.3 µM and topotecan 0.26 µM. Using One-way ANOVA, we observed 14 significantly altered metabolites compared to those cells treated with DMSO. For combination treatment (paclitaxel and topotecan), 10 metabolites were significantly dysregulated. The sparse partial least squares-discriminant analysis (sPLS-DA) showed minimal overlapping, indicating a difference between the four groups. While for proteomics, a total of 79 proteins were significantly dysregulated among the groups. These findings can aid in identifying new biomarkers associated with the utilized drugs and creating a map for targeted therapy. EIF3F, GNB2L1, HINT2, and RPA3 were shown to be significantly upregulated in the combination group when compared to the control. Moreover, ribosome, apoptosis, HIF-1 signaling, arginine and proline, glutathione, purine metabolism, apelin signaling pathway, and glycolysis were significantly altered in the combination group.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Brain Cancer

SUBMITTER: Core Facility

LAB HEAD: Mohammad Harb Semreen

PROVIDER: PXD052027 | Pride | 2025-05-07

REPOSITORIES: Pride

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Multi-omics analysis revealed significant metabolic changes in brain cancer cells treated with paclitaxel and/or topotecan.

Semreen Ahlam M AM Alsoud Leen Oyoun LO Semreen Mohammad H MH Ahmed Munazza M Al-Hroub Hamza M HM El-Awady Raafat R Ramadan Wafaa S WS Abuhelwa Ahmad A Bustanji Yasser Y Soares Nelson C NC Alzoubi Karem H KH

Heliyon 20241018 21

Glioblastoma (GBM) stands as the most common primary malignant brain tumor. Despite the best standard therapies, GBM survivors have a brief survival time, about 24 months on average. The treatment is troublesome because the cancer cells may not respond well to specific therapies as they grow within an extensive network of blood vessels. Our study aims to evaluate the impact of paclitaxel 5.3 μg/mL and topotecan 0.26 μM solely and in pairwise combination on the resultant metabolic and proteomic s ...[more]

PMID: 39524752

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Project description:Despite decades of effort, pancreatic adenocarcinoma (PDAC) remains an intractable clinical challenge. An insufficient understanding of mechanisms underlying tumor cell responses to chemotherapy contributes significantly to the lack of effective treatment regimens. Here, paclitaxel, a first-line chemotherapeutic agent, was observed to interact synergistically with birinapant, a Second Mitochondrial-derived Activator of Caspases mimetic. Therefore, we investigated molecular-level drug interaction mechanisms using comprehensive, reproducible, and well-controlled ion-current-based MS1 quantification (IonStar). In a set of 40 biological samples, we compared temporal proteomic responses of PDAC cells treated with birinapant and paclitaxel, alone and combined. Using stringent criteria (e.g. strict false-discovery-rate FDR control, 2 peptides/protein), we quantified 4069 unique proteins confidently (99.8% without any missing data), and 541 proteins were significantly altered in the three treatment groups with a FDR of <1%. Interestingly, most of these proteins were altered only by combined birinapant/paclitaxel, and these predominantly represented three biological processes: mitochondrial function, cell growth and apoptosis, and cell cycle arrest. Proteins responsible for activation of oxidative phosphorylation, fatty acid β-oxidation, and inactivation of aerobic glycolysis were altered largely by combined birinapant/paclitaxel compared to single drugs, suggesting that the Warburg effect, which is employed by PDAC cells for survival and proliferation, was alleviated by the combination treatment. Metabolic profiling confirmed substantially greater suppression of the Warburg effect by the combined agents compared to either drug alone. Western blot analysis confirmed changes in apoptosis/survival signaling pathways, such as inhibition of PI3K/AKT, JAK/STAT, and MAPK/ERK signal transduction, as well as induction of G2/M arrest, and the drug combination induced much more apoptosis than did single agents. Overall, this in-depth, large-scale proteomics study provided novel insights into molecular mechanisms underlying synergy of combined birinapant/paclitaxel, and describes a proteomics/informatics pipeline that can be applied broadly to the development of cancer drug combination regimens.

			Action	DRS
	U87-A1-01-4630.d.zip	Other
	U87-A1-02-4632.d.zip	Other
	U87-A2-01-4635.d.zip	Other
	U87-A3-01-4640.d.zip	Other
	U87-A3-02-4641.d.zip	Other