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):

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