Dataset Information

(Phospho-)proteomic analysis of gemcitabine resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment response

ABSTRACT: Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). The present study aimed to evaluate the proteome and phosphoproteome of gemcitabine-sensitive and -resistant PDAC cells to identify novel targets and predictive biomarkers.The oncogenic capabilities of sensitive and resistant PDAC cells were evaluated in vitro and in vivo. Cultured cells were subsequently analysed by label-free mass spectrometry. Differential proteins and phosphopeptides were evaluated for Gene Ontology and predictive and / or prognostic biomarker potential by immunohistochemistry of tissue microarrays (TMAs). Differential analyses showed that resistant proteins are associated with membrane organization and microtubule regulation. Importantly, resistant cells displayed an increased sensitivity for paclitaxel treatment in vitro (p < 0.001) and nab-paclitaxel had a strong anti-tumour efficacy in vivo. Microtubule-associated protein 2 (MAP2) was found to be highly upregulated and phosphorylated in resistant cells. The identified resistance marker MAP2 emerged as a novel prognostic marker in PDAC patients treated with gemcitabine.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Ductal Cell

DISEASE(S): Pancreatic Ductal Carcinoma

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD010112 | Pride | 2019-06-19

REPOSITORIES: Pride

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Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.

Le Large Tessa Ya Sung TYS El Hassouni Btissame B Funel Niccola N Kok Bart B Piersma Sander R SR Pham Thang V TV Olive Kenneth P KP Kazemier Geert G van Laarhoven Hanneke W M HWM Jimenez Connie R CR Bijlsma Maarten F MF Giovannetti Elisa E

Therapeutic advances in medical oncology 20190510

<h4>Background</h4>Chemoresistance hampers the treatment of patients suffering from pancreatic ductal adenocarcinoma (PDAC). Here we aimed to evaluate the (phospho)proteome of gemcitabine-sensitive and gemcitabine-resistant PDAC cells to identify novel therapeutic targets and predictive biomarkers.<h4>Methods</h4>The oncogenic capabilities of gemcitabine-sensitive and resistant PDAC cells were evaluated <i>in vitro</i> and <i>in vivo</i>. Cultured cells were analyzed by label-free proteomics. Di ...[more]

PMID: 31205498

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Project description:Chemoresistance to gemcitabine limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an antibody drug conjugate (ADC) -like agent, EGFR/HER2 dual-targeting ligand-based lidamycin (DTLL), and studied the effect of DTLL combined with gemcitabine and the potential role of SMAD4 in the chemoresistance of PDAC. On the basis of SMAD4 profiles in in vitro and in vivo models, we investigated the antitumor effects of DTLL, gemcitabine and their combination, followed with mechanistic characterization. The results suggested that DTLL combination treatment with gemcitabine significantly repressed tumors with remarkably enhanced efficacy as compared to gemcitabine or DTLL alone given in either SMAD4-deficient/gemcitabine-resistant or SMAD4-sufficient/gemcitabine-sensitive cell line derived xenograft (CDX) and patient derived xenograft (PDX) tumors, respectively. Functional studies indicated that SMAD4 genetic status is responsible for SMAD4 protein level which determines different cellular susceptibility of PDAC. R100T mutation contributes to loss of SMAD4 protein and function with rapid protein degradation, leading to resistance to gemcitabine in PDAC cells. Moreover, DTLL significantly altered the protein half-life time and level of mutant and wild-type SMAD4 by inhibiting protein degradation at different velocities and distinctly changing the interaction of SMAD4 with TRIM33. Mechanism studies implied that DTLL combinational treatment might not only prevent from neoplastic proliferation via blockage of ATK/mTOR signaling and anti-apoptotic proteins (Bcl-2 and MCL1) mediated by impaired NF-B function in SMAD4-sufficient/gemcitabine-sensitive PDAC cells, but also restore the bioactivity of SMAD4 as a tumor suppressor to trigger its downstream NF-B-regulated signaling of cell apoptosis in SMAD4-deficient/gemcitabine-resistant tumors. In conclusion, SMAD4 is the key central mediator of not only the occurrence and development but also susceptibility in PDAC. DTLL sensitized gemcitabine efficacy via distinct action mechanisms based on SMAD4 profiles in SMAD4-sufficient/gemcitabine-sensitive and SMAD4-deficient/-resistant PDAC, respectively. Our findings provide insight into a rational SMAD4-directed precision treatment strategy and reveal a promising DTLL combination therapy to overcome chemoresistance in gemcitabine-resistant PDAC.

Dataset Information

(Phospho-)proteomic analysis of gemcitabine resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment response

Publications

Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment.

Similar Datasets

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