Comparative proteome analysis across non-small cell lung cancer cell lines

Grundner-Culemann, Kathrin; Dybowski, J. Nikolaj; Klammer, Martin; Tebbe, Andreas; Schaab, Christoph; Daub, Henrik

doi:10.1016/j.jprot.2015.09.003

Cited by 6 publications

(6 citation statements)

References 55 publications

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“…However, which HSD17B11-generated metabolites are involved and how the Arg283Gln variant impacts on HSD17B11 activity is currently unknown. HSD17B11 is nearly ubiquitously expressed ( Brereton et al, 2001 ; Chai et al, 2003 ), but is also overexpressed in some human malignancies, including advanced prostate cancer and non-small cell lung cancer cell lines, as compared to normal tissues or cell lines ( Grundner-Culemann et al, 2016 ; Nakamura et al, 2009 ). However, the potential role for HSD17B11 in cancer progression remains to be established.…”

Section: Discussionmentioning

confidence: 99%

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Demange

Joly

Marcoux

et al. 2022

eLife

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Hundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs.

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Section: Discussionmentioning

confidence: 99%

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Demange

Joly

Marcoux

et al. 2022

eLife

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“…In spite of the importance of KRas mutants in cancer biology, there are no reports to date on in-depth proteomic profiling of the surface of cancer cells expressing KRas mutants. There have been a few proteomic studies targeting whole-cell lysate of cancer cells expressing oncogenic Ras [94, 95]. …”

Section: Discussionmentioning

confidence: 99%

Comparative proteomics of a model MCF10A-KRasG12V cell line reveals a distinct molecular signature of the KRasG12V cell surface

Chan

Waters

et al. 2016

Oncotarget

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Oncogenic Ras mutants play a major role in the etiology of most aggressive and deadly carcinomas in humans. In spite of continuous efforts, effective pharmacological treatments targeting oncogenic Ras isoforms have not been developed. Cell-surface proteins represent top therapeutic targets primarily due to their accessibility and susceptibility to different modes of cancer therapy. To expand the treatment options of cancers driven by oncogenic Ras, new targets need to be identified and characterized at the surface of cancer cells expressing oncogenic Ras mutants. Here, we describe a mass spectrometry–based method for molecular profiling of the cell surface using KRasG12V transfected MCF10A (MCF10A-KRasG12V) as a model cell line of constitutively activated KRas and native MCF10A cells transduced with an empty vector (EV) as control. An extensive molecular map of the KRas surface was achieved by applying, in parallel, targeted hydrazide-based cell-surface capturing technology and global shotgun membrane proteomics to identify the proteins on the KRasG12V surface. This method allowed for integrated proteomic analysis that identified more than 500 cell-surface proteins found unique or upregulated on the surface of MCF10A-KRasG12V cells. Multistep bioinformatic processing was employed to elucidate and prioritize targets for cross-validation. Scanning electron microscopy and phenotypic cancer cell assays revealed changes at the cell surface consistent with malignant epithelial-to-mesenchymal transformation secondary to KRasG12V activation. Taken together, this dataset significantly expands the map of the KRasG12V surface and uncovers potential targets involved primarily in cell motility, cellular protrusion formation, and metastasis.

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“…Human NSCLC cell lines PGCL3, SK-MES-1, NCI-H460, A549, NCI-1299 and immortalized human normal bronchial epithelium cell line 16HBE were purchased from ATCC [29]. A549 cells were cultured in Dulbecco’s Modified Eagle Medium (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

Shen

Zhang

et al. 2017

Cell Physiol Biochem

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Background: The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Methods: Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata) on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC) cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol’s inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol’s efficacy in vivo. Results: Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. Conclusion: These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

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Comparative proteome analysis across non-small cell lung cancer cell lines

Cited by 6 publications

References 55 publications

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species

Comparative proteomics of a model MCF10A-KRasG12V cell line reveals a distinct molecular signature of the KRasG12V cell surface

Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

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