The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells

Autor: Nora Diéguez-Martínez, Héctor Pérez-Montoyo, Guillermo Velasco, Ana Oaknin, Josefina Casas, Tatiana Erazo, Carles Domenech, Pau Muñoz-Guardiola, Cristina Muñoz-Pinedo, Sonia Solé, Guillermo Yoldi, Margarita Romeo, Teresa Moran, Miguel F. Segura, Marc Yeste-Velasco, Gemma Fabriàs, Joaquim Bosch-Barrera, José Luis Abad, Elisabet Megías-Roda, Sergio Espinosa-Gil, Jose M. Lizcano, Jose Alfon
Přispěvatelé: Ministerio de Economía y Competitividad (España), Fabriàs, Gemma [0000-0001-7162-3772], Fabriàs, Gemma
Rok vydání: 2020
Předmět:
Zdroj: Autophagy
r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
instname
Digital.CSIC. Repositorio Institucional del CSIC
ISSN: 1554-8635
1554-8627
0336-6480
DOI: 10.1080/15548627.2020.1761651
Popis: ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased DDIT3 and TRIB3 mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer.
This work was supported by the Centre for Industrial Technological Development [CDTI,INNOGLOBAL/20171061]; European Regional Development Fund [PI18/00442 and PI15/00339]; European Regional Development Fund [INNPACTO/IPT-2012-0614-010000, RETOS RTC-2017-6261-1, SAF2015-64237-R]; Fundació la Marató de TV3 [20134031]; H2020 Marie Skłodowska-Curie Actions [TRAIN GA721532]; Instituto de Salud Carlos III [PI15/00339]; Instituto de Salud Carlos III [PI18/00442]; Ministerio de Ciencia, Innovación y Universidades [CTQ2017- 85378-R]; Ministerio de Economía y Competitividad [RTC-2015-3821-1]; Ministerio de Economía y Competitividad [RTC-2017-6261-1]; Ministerio de Economía y Competitividad [EMP-TU-2015-4576]; Ministerio de Economía y Competitividad [RETOS RTC-2017-6261-1]; Ministerio de Economía y Competitividad [BFU2016-78154-R]; Ministerio de Economía y Competitividad [INNPACTO/IPT-2012-0614-010000]; Ministerio de Economía y Competitividad [SAF2015-64237-R]; Ministerio de Economía y Competitividad [RTC-2014-1532-1].
Databáze: OpenAIRE
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