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Autor/a:
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Llobet Navàs, David; Eritja Sánchez, Núria; Domingo, Mónica; Bergadà Bertran, Laura; Mirantes Barbeito, Cristina; Santacana Espasa, Maria; Pallares, Judit; Macià Armengol, Anna; Yeramian Hakim, Andree; Encinas Martín, Mario; Moreno-Bueno, Gema; Palacios, José; Lewis, Robert E.; Matias-Guiu, Xavier; Dolcet Roca, Xavier
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Notas:
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The Raf/MEK/extracellular signal-regulated kinase
(ERK) pathway participates in many processes altered
in development and progression of cancer in human
beings such as proliferation, transformation, differentiation,
and apoptosis. Kinase suppressor of Ras 1
(KSR1) can interact with various kinases of the Raf/
MEK/extracellular signal-regulated kinase pathway to
enhance its activation. The role of KSR1 in endometrial
carcinogenesis was investigated. cDNA and tissue
microarrays demonstrated that expression of KSR1
was up-regulated in endometrial carcinoma. Furthermore,
inhibition of KSR1 expression by specific small
hairpin RNA resulted in reduction of both proliferation
and anchorage-independent cell growth properties
of endometrial cancer cells. Because inhibition of
apoptosis has a pivotal role in endometrial carcinogenesis,
the effects of KSR1 in regulation of tumor
necrosis factor–related apoptosis-inducing ligand
(TRAIL)–induced apoptosis were investigated. KSR1
knock-down sensitized resistant endometrial cell
lines to both TRAIL- and Fas-induced apoptosis. Sensitization
to TRAIL and agonistic anti-Fas antibody was caused by down-regulation of FLIP (FLICE-inhibitory
protein). Also investigated was the molecular
mechanism by which KSR1 regulates FLIP protein levels.
It was demonstrated that KSR1 small hairpin RNA
did not affect FLIP transcription or degradation.
Rather, FLIP down-regulation was caused by Fas-associated
death domain protein–dependent inhibition of
FLIP translation triggered after TRAIL stimulation in
KSR1-silenced cells. Re-expression of heterologous
KSR1 in cells with down-regulated endogenous KSR1
restored FLIP protein levels and TRAIL resistance. In
conclusion, KSR1 regulates endometrial sensitivity to
TRAIL by regulating FLIP levels. |
