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

Authors: 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.
Article Title: Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis
Abstract: 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.
Journal Title: Oncogene
Volume: 31
Issue: 34
ISSN: 1476-5594; 0950-9232
Publisher: Unknown  
Journal Place: England
Date Published: 2012
Start Page: 3889
End Page: 3900
Language: eng
Notes: LR: 20130627; GR: CA120881/CA/NCI NIH HHS/United States; GR: DK37871/DK/NIDDK NIH HHS/United States; GR: GM059167/GM/NIGMS NIH HHS/United States; GR: GM30324/GM/NIGMS NIH HHS/United States; GR: R01 DK037871-29/DK/NIDDK NIH HHS/United States; GR: R01 GM030324-34/GM/NIGMS NIH HHS/United States; GR: R01 GM059167-12/GM/NIGMS NIH HHS/United States; GR: R37 GM030324-30/GM/NIGMS NIH HHS/United States; GR: U54 CA156735-02/CA/NCI NIH HHS/United States; GR: U54CA156735/CA/NCI NIH HHS/United States; JID: 8711562; 0 (Isoenzymes); EC (MAP Kinase Kinase Kinase 2); EC (MAP Kinase Kinase Kinases); EC (mitogen-activated protein kinase kinase kinase 11); EC (Mitogen-Activated Protein Kinase Kinases); NIHMS334582; OID: NLM: NIHMS334582; OID: NLM: PMC3297722; 2011/12/05 [aheadofprint]; ppublish