Their findings, which have just been published in an article in Cell Reports, may lead to treatments for other cancers, as well as a variety of other diseases and types of neurological injuries.
“The motivation for our research was to study what controls the proliferation or expansion of a particular cell type, the cerebellar granule cell progenitor, that can give rise to a medulloblastoma,” said Nagi Ayad, Ph.D., associate professor of psychiatry and behavioral sciences, a member of the Center for Therapeutic Innovation and the Miami Project to Cure Paralysis, and the study’s corresponding author. “Although surgical resection, radiation and chemotherapy reduce tumor occurrence of some forms of medulloblastoma, other forms are resistant to treatment.”
The researchers studied a protein called CK1δ, which they found highly expressed in cerebellar granule cell progenitors. They demonstrated that CK1δ is required for proliferation of these progenitors. The authors also found that the expression level of this protein is altered in medulloblastoma. A significant discovery was that CK1δ is overexpressed in medulloblastoma at the protein level, not the mRNA level.
“That suggested that there is a mode of protein degradation of CK1δ that may be dysregulated in medulloblastoma,” said Ayad. “We identified how CK1δ protein is degraded or destroyed, and how this destruction is lowered in medulloblastoma to increase CK1δ protein levels.”
The degradation occurred via a ubiquitin ligase, called the Anaphase Promoting Complex/Cyclosome (APC/C), which tags proteins for destruction and is thought to be a tumor suppressor in several cancers. The researchers’ theory is that if APC/C activity goes down in medulloblastoma, it allows CK1δ levels to increase, which in turn stimulates excessive proliferation of medulloblastoma cells. They also demonstrated that small molecule CK1δ inhibitors are effective at reducing the growth of medulloblastoma in mouse models.
“The studies are directly related to medulloblastoma and glioblastoma research,” said Ayad, “but CK1δ is a target in multiple cancers. CK1δ is also involved in neurite outgrowth and circadian rhythm, and is a target in psychiatric disease, alcoholism, and Alzheimer’s disease. It may also be a target in spinal cord injury and traumatic brain injury. It will be important to determine if this mechanism of protein destruction of CK1δ by APC/C is relevant for diseases and indications outside of cancer.”
The next step, said Ayad, is to test small molecule CK1δ inhibitors in medulloblastoma and glioblastoma patient-derived xenografts and to help move brain penetrant CK1 inhibitors into clinical trials for brain tumors.
The first author of the study is Clara Penas, Ph.D., a research associate in the Ayad laboratory. Additional Miller School authors of the journal article are Marie Maloof, a Ph.D. candidate in the Neuroscience Program; Jun Long, a Ph.D. candidate in the Molecular Oncology Research Program; David J. Robbins, Ph.D., professor of surgery in the DeWitt Daughtry Family Department of Surgery’s Division of Surgical Oncology; and Bin Li, Ph.D., a post-doctoral fellow in Robbins’ laboratory.
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