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

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

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Projekt

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Návaznosti

Z - Vyzkumny zamer (s odkazem do CEZ)

Rok uplatnění

2005

Kód důvěrnosti údajů

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

Název periodika

FEBS Letters

ISSN

0014-5793

e-ISSN

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Svazek periodika

579

Číslo periodika v rámci svazku

19

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

4149-4158

Kód UT WoS článku

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EID výsledku v databázi Scopus

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