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SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy
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SYSNO ASEP 0542237 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy Author(s) Ezrová, Zuzana (BTO-N) ORCID
Nahácka, Zuzana (BTO-N)
Štursa, Jan (BTO-N)
Werner, Lukáš (BTO-N)
Vlčák, Erik (UMG-J)
Králová Viziová, Petra (UMG-J)
Berridge, M.V. (NZ)
Sedláček, Radislav (UMG-J) RID
Zobalová, Renata (BTO-N) RID
Rohlena, Jakub (BTO-N) RID, ORCID
Boukalová, Štěpána (BTO-N)
Neužil, Jiří (BTO-N) RIDNumber of authors 12 Source Title Oncogene. - : Springer - ISSN 0950-9232
Roč. 40, č. 14 (2021), s. 2539-2552Number of pages 24 s. Language eng - English Country GB - United Kingdom Keywords biguanide derivative ; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) ; Smad4 protein Subject RIV EB - Genetics ; Molecular Biology OECD category Genetics and heredity (medical genetics to be 3) Subject RIV - cooperation Institute of Molecular Genetics - Genetics ; Molecular Biology R&D Projects NV16-31604A GA MZd - Ministry of Health (MZ) GA19-20553S GA ČR - Czech Science Foundation (CSF) GA20-18513S GA ČR - Czech Science Foundation (CSF) GJ20-11724Y GA ČR - Czech Science Foundation (CSF) GA18-02550S GA ČR - Czech Science Foundation (CSF) EF16_027/0008353 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LO1220 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2015062 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001775 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018126 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001789 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015861 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) ED2.1.00/19.0395 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support BTO-N - RVO:86652036 ; UMG-J - RVO:68378050 UT WOS 000626396000002 EID SCOPUS 85102194707 DOI 10.1038/s41388-021-01726-4 Annotation Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor beta (TGF beta) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGF beta-treatment and the loss of SMAD4, a downstream member of TGF beta signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGF beta-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGF beta signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGF beta signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2022 Electronic address https://www.nature.com/articles/s41388-021-01726-4?elqTrackId=c7cc7e8c0df94ff7a61453bf09cfb167
Number of the records: 1