Dataset Information

Cellular Interactome Dynamics during Paclitaxel Treatment.

ABSTRACT: Cell-cycle inhibitors, including paclitaxel, are among the most widely used and effective cancer therapies. However, several challenges limit the success of paclitaxel, including drug resistance and toxic side effects. Paclitaxel is thought to act primarily by stabilizing microtubules, locking cells in a mitotic state. However, the resulting cytotoxicity and tumor shrinkage rates observed cannot be fully explained by this mechanism alone. Here we apply quantitative chemical cross-linking with mass spectrometry analysis to paclitaxel-treated cells. Our results provide large-scale measurements of relative protein levels and, perhaps more importantly, changes to protein conformations and interactions that occur upon paclitaxel treatment. Drug concentration-dependent changes are revealed in known drug targets including tubulins, as well as many other proteins and protein complexes involved in apoptotic signaling and cellular homeostasis. As such, this study provides insight into systems-level changes to protein structures and interactions that occur with paclitaxel treatment.

SUBMITTER: Chavez JD

PROVIDER: S-EPMC6910234 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Cellular Interactome Dynamics during Paclitaxel Treatment.

Chavez Juan D JD Keller Andrew A Zhou Bo B Tian Rong R Bruce James E JE

Cell reports 20191101 8

Cell-cycle inhibitors, including paclitaxel, are among the most widely used and effective cancer therapies. However, several challenges limit the success of paclitaxel, including drug resistance and toxic side effects. Paclitaxel is thought to act primarily by stabilizing microtubules, locking cells in a mitotic state. However, the resulting cytotoxicity and tumor shrinkage rates observed cannot be fully explained by this mechanism alone. Here we apply quantitative chemical cross-linking with ma ...[more]

PMID: 31747606

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Project description:BackgroundIn syllids (Annelida, Syllidae), the regenerative blastema was subject of many studies in the mid and late XXth century. This work on syllid regeneration showed that the blastema is developed by a process of dedifferentiation of cells near the wound, followed by their proliferation and redifferentiation (cells differentiate to the original cell type) or, in some specific cases, transdifferentiation (cells differentiate to a cell type different from the original). Up to date, participation of stem cells or pre-existing proliferative cells in the blastema development has never been observed in syllids. This study provides the first comprehensive description of Syllis malaquini's regenerative capacity, including data on the cellular proliferation dynamics by using an EdU/BrdU labelling approach, in order to trace proliferative cells (S-phase cells) present before and after operation.ResultsSyllis malaquini can restore the anterior and posterior body from different cutting levels under experimental conditions, even from midbody fragments. Our results on cellular proliferation showed that S-phase cells present in the body before bisection do not significantly contribute to blastema development. However, in some specimens cut at the level of the proventricle, cells in S-phase located in the digestive tube before bisection participated in regeneration. Also, our results showed that nucleus shape allows to distinguish different types of blastemal cells as forming specific tissues. Additionally, simultaneous and sequential addition of segments seem to occur in anterior regeneration, while only sequential addition was observed in posterior regeneration. Remarkably, in contrast with previous studies in syllids, sexual reproduction was not induced during anterior regeneration of amputees lacking the proventricle, a foregut organ widely known to be involved in the stolonization control.ConclusionsOur findings led us to consider that although dedifferentiation and redifferentiation might be more common, proliferative cells present before injury can be involved in regenerative processes in syllids, at least in some cases. Also, we provide data for comparative studies on resegmentation as a process that differs between anterior and posterior regeneration; and on the controversial role of the proventricle in the reproduction of different syllid lineages.

Project description:BACKGROUND: In cystic fibrosis (CF) patients, the upper airways display the same ion channel defect as evident in the lungs, resulting in chronic inflammation and infection. Recognition of the sinonasal area as a site of first and persistent infection with pathogens, such as Pseudomonas aeruginosa, reinforces the "one-airway" hypothesis. Therefore, we assessed the effect of systemic antibiotics against pulmonary pathogens on sinonasal inflammation. METHODS: Nasal lavage fluid (NLF) from 17 CF patients was longitudinally collected prior to and during elective intravenous (i.v.) antibiotic treatment to reduce pathogen burden and resulting inflammation (median treatment time at time of analysis: 6 days). Samples were assessed microbiologically and cytologically. Cytokine and chemokine expression was measured by Cytometric Bead Array and ELISA (interleukin (IL)-1?, IL-6, IL-8, MPO, MMP9, RANTES and NE). Findings were compared with inflammatory markers from NLF obtained from 52 healthy controls. RESULTS: Initially, the total cell count of the NLF was significantly higher in CF patients than in controls. However after i.v. antibiotic treatment it decreased to a normal level. Compared with controls, detection frequencies and absolute concentrations of MPO, IL-8, IL-6 and IL-1? were also significantly higher in CF patients. The detection frequency of TNF was also higher. Furthermore, during i.v. therapy sinonasal concentrations of IL-6 decreased significantly (P = 0.0059), while RANTES and MMP9 levels decreased 10-fold and two-fold, respectively. PMN-Elastase, assessed for the first time in NFL, did not change during therapy. CONCLUSIONS: Analysis of NLF inflammatory markers revealed considerable differences between controls and CF patients, with significant changes during systemic i.v. AB treatment within just 6 days. Thus, our data support further investigation into the collection of samples from the epithelial surface of the upper airways by nasal lavage as a potential diagnostic and research tool.

Dataset Information

Cellular Interactome Dynamics during Paclitaxel Treatment.

Publications

Cellular Interactome Dynamics during Paclitaxel Treatment.

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