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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F21%3A00542237" target="_blank" >RIV/86652036:_____/21:00542237 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/21:00542237 RIV/00216208:11310/21:10440414

Výsledek na webu

<a href="https://www.nature.com/articles/s41388-021-01726-4?elqTrackId=c7cc7e8c0df94ff7a61453bf09cfb167" target="_blank" >https://www.nature.com/articles/s41388-021-01726-4?elqTrackId=c7cc7e8c0df94ff7a61453bf09cfb167</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41388-021-01726-4" target="_blank" >10.1038/s41388-021-01726-4</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10603 - Genetics and heredity (medical genetics to be 3)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Oncogene

ISSN

0950-9232

e-ISSN

1476-5594

Svazek periodika

40

Číslo periodika v rámci svazku

14

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

24

Strana od-do

2539-2552

Kód UT WoS článku

000626396000002

EID výsledku v databázi Scopus

2-s2.0-85102194707