Tumorigenesis and neurodegeneration: two sides of the same coin?

Abstract

SummaryDysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxiatelangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.

Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

“…However, ablation of parkin expression induced apoptotic cell death in human dopaminergic cells (31). These results suggest that in terminally differentiated cells, including neurons, reactivation of the cell cycle induces apoptosis rather than proliferation (32). Therefore, parkin may exert different effects depending on the cell type and cell cycle status.…”

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

“…In this context, it has been suggested that reentry in the cell cycle, together with oxidative stress production, constitutes a component of the apoptotic cascade in the process of neuronal cell death through the expression of the transcription factor E2F-1 [25,[52][53][54][55][56][57][58]. Currently, the mechanism responsible for cell-cycle activation is unknown and its place in the apoptotic route, prior to the activation of the intrinsic (mitochondrial) programmed cell-death pathway, still requires clarification.…”

Parkin Is Dispensable for Mitochondrial Function, but Its Ubiquitin Ligase Activity Is Critical for Macroautophagy and Neurotransmitters: Therapeutic Potential beyond Parkinson's Disease

“…Parkin now seems to be a validated target to modulate autophagy and/or the proteasome, preventing the proliferation of cancer cells [20]. Relevant to cancer, the early transcription factor and key regulator of cell cycle c-Jun [21] interacts with Parkin to prevent neural apoptosis [22]. c-Jun activity (at least in part) is controlled by its interaction with the tumor repressor p53 [23], the dysfunction of which is linked to tumorigenesis [24].…”