title: KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels.
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.
authors: Oncologic Pathology Group, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, Departament de Ciencies Mediques Basiques, Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain.
authors: David
authors: D
authors: Llobet
authors: Nuria
authors: N
authors: Eritja
authors: Monica
authors: M
authors: Domingo
authors: Laura
authors: L
authors: Bergada
authors: Cristina
authors: C
authors: Mirantes
authors: Maria
authors: M
authors: Santacana
authors: Judit
authors: J
authors: Pallares
authors: Anna
authors: A
authors: Macià
authors: Andree
authors: A
authors: Yeramian
authors: Mario
authors: M
authors: Encinas
authors: Gema
authors: G
authors: Moreno-Bueno
authors: Jose
authors: J
authors: Palacios
authors: Robert E
authors: RE
authors: Lewis
authors: Xavier
authors: X
authors: Matias-Guiu
authors: Xavi
authors: X
authors: Dolcet
mesh_terms: D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis*; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D011494:Protein Kinases / Q000096:biosynthesis*; D012313:RNA / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018076:DNA, Complementary; D053221:TNF-Related Apoptosis-Inducing Ligand; D012313:RNA; D011494:Protein Kinases; C097199:KSR-1 protein kinase