Dataset Information

Increasing Pexophagy as an Unconventional Mode to Kill Cancer Cells

ABSTRACT: The autophagy-mediated degradation of peroxisomes, pexophagy, serves as a rheostat for peroxisome homeostasis. However, disturbing this process has yet to be investigated in the context of therapy treatment and resistance in cancer. In Vorinostat (Vor)-resistant lymphoma (B8) cells, an autophagosome enrichment procedure, followed by mass spectrometry (MS), revealed an abundance of peroxisomal proteins, indicative of elevated pexophagy. This was validated by immunofluorescence colocalization and co-immunoprecipitation of PEX5 with the pexophagy receptor p62. Using Vor-resistant B8 cells, we triggered apoptosis by genetically silencing PEX1, PEX6 and PEX26, members of the exportomer complex, which negatively regulates pexophagy. To further explore PEX26 in other model systems, we genetically silenced the exportomer component in A549 (lung adenocarcinoma), 1205Lu (melanoma) and in 1205Lu cells with acquired resistance to MAPK-targeted therapies (VCR5). Here, we observed that silencing PEX26 promotes therapy sensitivity under otherwise therapy-resistant conditions. Using gene expression data from lymphoma (DLBCL), melanoma and lung adenocarcinoma cohorts, we found that low gene expression of PEX26, a component of the “negative regulation of pexophagy” signature, was significantly associated with prolonged patient survival. Clinically, gene expression levels of this signature could be utilized as a prognostic indicator in DLBCL, lung adenocarcinoma, melanoma, and perhaps other cancers. In conclusion, we provide precedence for the development and use of therapies that promote pexophagy in cancer. Furthermore, the MS-based identification of autophagosome cargos provides a platform towards identifying proteins unique to pro-death and pro-survival autophagosomes in cancer model systems, which could illuminate therapeutic use and development.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Blood Cell, Lung

DISEASE(S): Acute Leukemia

SUBMITTER: Francois-Michel Boisvert

LAB HEAD: Sonia V. del Rincón

PROVIDER: PXD013926 | Pride | 2022-08-11

REPOSITORIES: Pride

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Silencing PEX26 as an unconventional mode to kill drug-resistant cancer cells and forestall drug resistance.

Dahabieh Michael S MS Huang Fan F Goncalves Christophe C Flores González Raúl Ernesto RE Prabhu Sathyen S Bolt Alicia A Di Pietro Erminia E Khoury Elie E Heath John J Xu Zi Yi ZY Rémy-Sarrazin Joelle J Mann Koren K KK Orthwein Alexandre A Boisvert François-Michel FM Braverman Nancy N Miller Wilson H WH Del Rincón Sonia V SV

Autophagy 20210621 3

Promoting the macroautophagy/autophagy-mediated degradation of specific proteins and organelles can potentially be utilized to induce apoptosis in cancer cells or sensitize tumor cells to therapy. To examine this concept, we enriched for autophagosomes from histone deacetylase inhibitor (HDACi)-sensitive U937 lymphoma cells and isogenic HDACi-resistant cells. Mass spectrometry on autophagosome-enriched fractions revealed that HDACi-resistant cells undergo elevated pexophagy, or autophagy of the ...[more]

PMID: 34074205

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Project description:Human histomonocytic U937 cells exhibit macrophage-like properties after phorbol ester stimulation. Accumulating evidence demonstrated that remarkable number of transcripts changed in their amount at total RNA levels. However, post-transcriptional regulation has not been fully elucidated in this model. Thus, we compared expression profiles between polysomal and cytoplasmic RNAs before and after phorbol 12-myristate 13-acetate stimulation (48h, 32nM). Table 1: Detailed description of the expression data of human histomonocytic cell line U937 cells. Data of total cytoplasmic and polysomal fractions before and after PMA stimulation is shown. This table contains all spot data except: 1) saturated spots, 2) undetectable spots, 3) stained spots, and 4) spots only detected in less than one samples. Column A: Gene symbol (âI_xxxxxxâ is corresponding to EST clones); Column B: Genbank accession no. Column C: Description; Column D: Average value of expression levels in total cytoplasmic fraction in the absence of PMA; Column E: Average value of expression levels in total cytoplasmic fraction in the presence of PMA (32nM, 48h); Column F: Average value of expression levels in polysomal fraction in the absence of PMA; Column G: Average value of expression levels in polysomal fraction in the presence of PMA; Column H: Expression ratio of polysome, PMA (-) to cytoplasm, PMA(-); Column I: Expression ratio of polysome, PMA (+) to cytoplasm, PMA(+); Column J: Expression ratio of cytoplasm, PMA (+) to cytoplasm, PMA(-); Column K: Expression ratio of polysome, PMA (+) to polysome, PMA(-); Column L: Different expression between polysome, PMA (-) and cytoplasm, PMA(-): different=1; Column M: Different expression between polysome, PMA (+) and cytoplasm, PMA(+): different=1; Column N: Different expression between cytoplasm, PMA (+) and cytoplasm, PMA(-): different=1; Column O: Different expression between polysome, PMA (+) and polysome, PMA(-): different=1; ; Table 2: Candidates post-transcriptionally regulated by PMA. We extracted 105 transcripts whose expression levels were altered only in either fraction accompanied by changes in polysome/cytoplasm expression ratio. Column A: Gene symbol (âI_xxxxxxâ is corresponding to EST clones); Column B: Genbank accession no. Column C: Description; Column D: Average value of expression levels in total cytoplasmic fraction in the absence of PMA; Column E Average value of expression levels in total cytoplasmic fraction in the presence of PMA; Column F: Average value of expression levels in polysomal fraction in the absence of PMA; Column G: Average value of expression levels in polysomal fraction in the presence of PMA; Column H: Expression ratio of polysome, PMA (-) to cytoplasm, PMA(-); Column I: Expression ratio of polysome, PMA (+) to cytoplasm, PMA(+); Column J: Expression ratio of cytoplasm, PMA (+) to cytoplasm, PMA(-); Column K: Expression ratio of polysome, PMA (+) to polysome, PMA(-)

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