Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis.

Cronan, M R; Nakamura, K; Johnson, N L; Granger, D A; Cuevas, B D; Wang, J-G; Mackman, N; Scott, J E; Dohlman, H G; Johnson, G L

Cronan, M R; Nakamura, K; Johnson, N L; Granger, D A; Cuevas, B D; Wang, J-G; Mackman, N; Scott, J E; Dohlman, H G; Johnson, G L.

Afiliación

Cronan MR; Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA.

Oncogene ; 31(34): 3889-900, 2012 Aug 23.

Article en En | MEDLINE | ID: mdl-22139075

RESUMEN

Analysis of patient tumors suggests that multiple MAP3 kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable short hairpin RNA (shRNA) knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo. These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5, are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. MEKK2 was required for epidermal growth factor receptor and Her2/Neu activation of ERK5, with ERK5 being required for metastasis. Loss of MLK3 expression increased mitotic infidelity and apoptosis in vitro. Knockdown of MEKK2 and MLK3 resulted in increased apoptosis in orthotopic xenografts relative to control tumors in mice, inhibiting both tumor growth and metastasis; MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development.

Asunto(s)

Neoplasias de la Mama/genética; Neoplasias Mamarias Experimentales/genética; Quinasas de Proteína Quinasa Activadas por Mitógenos/genética; Interferencia de ARN; Animales; Apoptosis/genética; Western Blotting; Neoplasias de la Mama/enzimología; Neoplasias de la Mama/patología; Línea Celular Tumoral; Supervivencia Celular/genética; Células HEK293; Humanos; Isoenzimas/genética; Isoenzimas/metabolismo; MAP Quinasa Quinasa Quinasa 2/genética; MAP Quinasa Quinasa Quinasa 2/metabolismo; Quinasas Quinasa Quinasa PAM/genética; Quinasas Quinasa Quinasa PAM/metabolismo; Neoplasias Mamarias Experimentales/enzimología; Neoplasias Mamarias Experimentales/patología; Ratones; Ratones SCID; Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo; Metástasis de la Neoplasia; Reacción en Cadena de la Polimerasa de Transcriptasa Inversa; Trasplante Heterólogo; Carga Tumoral/genética; Proteina Quinasa Quinasa Quinasa 11 Activada por Mitógeno

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Quinasas de Proteína Quinasa Activadas por Mitógenos / Interferencia de ARN / Neoplasias Mamarias Experimentales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google