Calmodulin-kinases regulate basal and estrogen stimulated medulloblastoma migration via Rac1.
Medulloblastoma is a highly prevalent pediatric central nervous system malignancy originating in the cerebellum, with a strong propensity for metastatic migration to the leptomeninges, which greatly increases mortality. While numerous investigations are focused on the molecular mechanisms of medulloblastoma histogenesis, the signaling pathways regulating migration are still poorly understood. Medulloblastoma likely arises from aberrant proliferative signaling in cerebellar granule precursor cells during development, and estrogen is a morphogen that promotes medulloblastoma cell migration. It has been previously shown that the calcium/calmodulin activated kinase kinase (CaMKK) pathway promotes cerebellar granule precursor migration and differentiation during normal cerebellar development via CaMKIV. Here we investigate the regulatory role of the CaMKK pathway in migration of the human medulloblastoma DAOY and cerebellar granule cells. Using pharmacological inhibitors and dominant negative approaches, we demonstrate that the CaMKK/CaMKI cascade regulates basal medulloblastoma cell migration via Rac1, in part by activation of the RacGEF, βPIX. Additionally, pharmacological inhibition of CaMKK blocks both the estrogen induced Rac1 activation and medulloblastoma migration. The CaMKK signaling module described here is one of the first reported calcium regulated pathways that modulates medulloblastoma migration. Since tumor dissemination requires cell migration to ectopic sites, this CaMKK pathway may be a putative therapeutic target to limit medulloblastoma metastasis.
Vollum Institute and Knight Cancer Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. davarem@ohsu.edu
Monika A
MA
Davare
Takeo
T
Saneyoshi
Thomas R
TR
Soderling
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles / Q000494:pharmacology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology; D053644:Naphthalimides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D011743:Pyrimidines / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000634:Aminoquinolines; D001562:Benzimidazoles; D002614:Chelating Agents; C506907:EHT 1864; D004791:Enzyme Inhibitors; D004967:Estrogens; D020662:Guanine Nucleotide Exchange Factors; C487513:NSC 23766; D053644:Naphthalimides; D011743:Pyrimidines; D011753:Pyrones; D011804:Quinolines; D064067:Rho Guanine Nucleotide Exchange Factors; C458525:STO 609; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D020830:rac1 GTP-Binding Protein