SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy

0542237 - BTÚ 2022 RIV GB eng J - Journal Article
Ezrová, Zuzana - Nahácka, Zuzana - Štursa, Jan - Werner, Lukáš - Vlčák, Erik - Králová Viziová, Petra - Berridge, M.V. - Sedláček, Radislav - Zobalová, Renata - Rohlena, Jakub - Boukalová, Štěpána - Neužil, Jiří
SMAD4 loss limits the vulnerability of pancreatic cancer cells to complex I inhibition via promotion of mitophagy.
Oncogene. Roč. 40, č. 14 (2021), s. 2539-2552. ISSN 0950-9232. E-ISSN 1476-5594
R&D Projects: GA MZd(CZ) NV16-31604A; GA ČR GA19-20553S; GA ČR(CZ) GA20-18513S; GA ČR(CZ) GJ20-11724Y; GA ČR(CZ) GA18-02550S; GA MŠMT(CZ) EF16_027/0008353; GA MŠMT(CZ) ED1.1.00/02.0109; GA MŠMT LO1220; GA MŠMT(CZ) LM2015062; GA MŠMT(CZ) EF16_013/0001775; GA MŠMT(CZ) LM2018126; GA MŠMT EF16_013/0001789; GA MŠMT EF18_046/0015861; GA MŠMT ED2.1.00/19.0395
Institutional support: RVO:86652036 ; RVO:68378050
Keywords : biguanide derivative * reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) * Smad4 protein
OECD category: Genetics and heredity (medical genetics to be 3); Genetics and heredity (medical genetics to be 3) (UMG-J)
Impact factor: 8.756, year: 2021
Method of publishing: Limited access
https://www.nature.com/articles/s41388-021-01726-4?elqTrackId=c7cc7e8c0df94ff7a61453bf09cfb167

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.
Permanent Link: http://hdl.handle.net/11104/0319702