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

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

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

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

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

Publication year

2021

Confidentiality

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

Name of the periodical

Oncogene

ISSN

0950-9232

e-ISSN

1476-5594

Volume of the periodical

40

Issue of the periodical within the volume

14

Country of publishing house

GB - UNITED KINGDOM

Number of pages

24

Pages from-to

2539-2552

UT code for WoS article

000626396000002

EID of the result in the Scopus database

2-s2.0-85102194707