Publication: Targeting protein methylation in pancreatic cancer cells results in KRAS signaling imbalance and inhibition of autophagy
Authors
Martí Díaz, Román ; Navarro, Ana ; Tolivia, Jorge ; Cabezas Herrera, Juan ; Montenegro Arce, María Fernanda ; Rodríguez López, José Neptuno ; Sánchez del Campo Ferrer, Luis
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Publisher
Springer Nature
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DOI
10.1038/s41419-023-06288-9
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info:eu-repo/semantics/bookPart
Description
©2023. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Published Manuscript version of a Published Work that appeared in final form in Cell Death & Disease. To access the final edited and published work see https://doi.org/10.1038/s41419-023-06288-9
Abstract
Pancreatic cancer cells with mutant KRAS require strong basal autophagy for viability and growth. Here, we observed that some processes that allow the maintenance of basal autophagy in pancreatic cancer cells are controlled by protein methylation. Thus, by maintaining the methylation status of proteins such as PP2A and MRAS, these cells can sustain their autophagic activity. Protein methylation disruption by a hypomethylating treatment (HMT), which depletes cellular S-adenosylmethionine levels while inducing S-adenosylhomocysteine accumulation, resulted in autophagy inhibition and endoplasmic reticulum stress-induced apoptosis in pancreatic cancer cells. We observed that by reducing the membrane localization of MRAS, hypomethylation conditions produced an imbalance in KRAS signaling, resulting in the partial inactivation of ERK and hyperactivation of the PI3K/AKT–mTORC1 pathway. Interestingly, HMT impeded CRAF activation by disrupting the ternary SHOC2 complex (SHOC2/MRAS/PP1), which functions as a CRAF-S259 holophosphatase. The demethylation events that resulted in PP2A inactivation also favored autophagy inhibition by preventing ULK1 activation while restoring the cytoplasmic retention of the MiT/TFE transcription factors. Since autophagy provides pancreatic cancer cells with metabolic plasticity to cope with various metabolic stress conditions, while at the same time promoting their pathogenesis and resistance to KRAS pathway inhibitors, this hypomethylating treatment could represent a therapeutic opportunity for pancreatic adenocarcinomas.
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Citation
Cell Death & Disease, Volumen: 14 ,nº: 761, 2023
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