HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway: an unexpected effect on TRAIL-induced apoptosis

Result code in IS VaVaI

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Result on the web

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DOI - Digital Object Identifier

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Result language

angličtina

Original language name

HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway: an unexpected effect on TRAIL-induced apoptosis

Original language description

We investigated whether HER2 downregulation by trastuzumab modulates the responsiveness of breast cancer cells to TRAIL. In contrast to increased response to TRAIL in SKBr3 cells, trastuzumab decreased the susceptibility of BT474 cells to TRAIL. This decrease was also observed after exogenous inhibition of PI3-K/Akt kinase, but not MEK/ MAPK. In BT474 cells, but not SKBr3 cells, inhibition of the HER2/ PI3K/Akt pathway resulted in downregulation of the pro-apoptotic receptors TRAIL-R1and TRAIL-R2, TRAIL-induced caspase-8 activation, Bid processing, drop of DeltaPsi(m), and PARP cleavage but not in caspase-9 activation, and these events were inhibited in HER2/PI3K/Akt-suppressed BT474 cells, which exhibited downregulation of Bcl-xL and increased response to mitomycin C. We show that HER2/PI3K/Akt pathway may play a specific pro-apoptotic role in certain cell type by inducing TRAIL-R1 and -R2 expression and thereby enhancing responsiveness to TRAIL.

Czech name

Oslabení signalizace HER2 trastuzumabem a potlačení dráhy PI3K/Akt: neočekávaný vliv na apoptózu vyvolanou TRAIL

Czech description

Zkoumali jsme, zda oslabení exprese HER2 trastuzumabem ovlivňuje reakci buněk nádoru prsu na TRAIL. Oproti zvýšené reakci na TRAIL u buněk SKBr3, u buněk BT474 trastuzumab citlivost vůči TRAIL snižoval. Toto snížení bylo také pozorováno po exogenní inhibici kinázy PI3-K/Akt, ale ne MEK/MAPK. U buněk BT474, ale ne u SKBr3, vedla inhibice dráhy HER2/PI3K/Akt ke snížené expresi proapoptotických receptorů TRAIL-R1 a TRAIL-R2, aktivaci kaspázy-8 vyvolané TRAIL, zpracování Bid, snížení DeltaPsi(m) a štěpení PARP, ale ne k aktivaci kaspázy-9, a tyto děje byly zastaveny u buněk BT474 s potlačenou signalizací HER2/PI3K/Akt, které vykazovaly sníženou expresi Bcl-xL a zvýšenou reakci na mitomycin C. Ukazujeme, že dráha HER2/PI3K/Akt může u určitého typu buněk hrát specifickou proapoptotickou roli indukcí exprese TRAIL-R1 a TRAIL-R2 a tím zvýšenou reaktivitou na TRAIL.

Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

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Project

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Continuities

Z - Vyzkumny zamer (s odkazem do CEZ)

Publication year

2005

Confidentiality

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

Name of the periodical

FEBS Letters

ISSN

0014-5793

e-ISSN

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Volume of the periodical

579

Issue of the periodical within the volume

19

Country of publishing house

GB - UNITED KINGDOM

Number of pages

10

Pages from-to

4149-4158

UT code for WoS article

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EID of the result in the Scopus database

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