KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels

David Llobet, Nuria Eritja, Monica Domingo, Laura Bergada, Cristina Mirantes, Maria Santacana, Judit Pallares, Anna Macià, Andree Yeramian, Mario Encinas, Gema Moreno-Bueno, Jose Palacios, Robert E Lewis, Xavier Matias-Guiu, Xavi Dolcet

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1529-1543
Number of pages15
JournalAmerican Journal of Pathology
Volume178
Issue number4
DOIs
StatePublished - Jan 1 2011

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CASP8 and FADD-Like Apoptosis Regulating Protein
Endometrial Neoplasms
Apoptosis
Extracellular Signal-Regulated MAP Kinases
Small Interfering RNA
KSR-1 protein kinase
Carcinogenesis
Fas-Associated Death Domain Protein
Down-Regulation
raf Kinases
TNF-Related Apoptosis-Inducing Ligand
MAP Kinase Kinase Kinases
Mitogen-Activated Protein Kinase Kinases
Protein Biosynthesis
Oligonucleotide Array Sequence Analysis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. / Llobet, David; Eritja, Nuria; Domingo, Monica; Bergada, Laura; Mirantes, Cristina; Santacana, Maria; Pallares, Judit; Macià, Anna; Yeramian, Andree; Encinas, Mario; Moreno-Bueno, Gema; Palacios, Jose; Lewis, Robert E; Matias-Guiu, Xavier; Dolcet, Xavi.

In: American Journal of Pathology, Vol. 178, No. 4, 01.01.2011, p. 1529-1543.

Research output: Contribution to journalArticle

Llobet, D, Eritja, N, Domingo, M, Bergada, L, Mirantes, C, Santacana, M, Pallares, J, Macià, A, Yeramian, A, Encinas, M, Moreno-Bueno, G, Palacios, J, Lewis, RE, Matias-Guiu, X & Dolcet, X 2011, 'KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels', American Journal of Pathology, vol. 178, no. 4, pp. 1529-1543. https://doi.org/10.1016/j.ajpath.2010.12.041
Llobet, David ; Eritja, Nuria ; Domingo, Monica ; Bergada, Laura ; Mirantes, Cristina ; Santacana, Maria ; Pallares, Judit ; Macià, Anna ; Yeramian, Andree ; Encinas, Mario ; Moreno-Bueno, Gema ; Palacios, Jose ; Lewis, Robert E ; Matias-Guiu, Xavier ; Dolcet, Xavi. / KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels. In: American Journal of Pathology. 2011 ; Vol. 178, No. 4. pp. 1529-1543.
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AU - Llobet, David

AU - Eritja, Nuria

AU - Domingo, Monica

AU - Bergada, Laura

AU - Mirantes, Cristina

AU - Santacana, Maria

AU - Pallares, Judit

AU - Macià, Anna

AU - Yeramian, Andree

AU - Encinas, Mario

AU - Moreno-Bueno, Gema

AU - Palacios, Jose

AU - Lewis, Robert E

AU - Matias-Guiu, Xavier

AU - Dolcet, Xavi

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N2 - 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.

AB - 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.

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