Molecular crosstalk between cancer and neurodegenerative diseases

Abstract

The progression of cancers and neurodegenerative disorders is largely defined by a set of molecular determinants that are either complementarily deregulated, or share remarkably overlapping functional pathways. A large number of such molecules have been demonstrated to be involved in the progression of both diseases. In this review, we particularly discuss our current knowledge on p53, cyclin D, cyclin E, cyclin F, Pin1 and protein phosphatase 2A, and their implications in the shared or distinct pathways that lead to cancers or neurodegenerative diseases. In addition, we focus on the interdependent regulation of brain cancers and neurodegeneration, mediated by intercellular communication between tumor and neuronal cells in the brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. Keywords Age-related diseases • Cell death • Cell survival • Redox system • Glioma • Neurotoxicity Abbreviations Aβ Amyloid-β AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionate APC/C Anaphase promoting complex/ cyclosome APP Amyloid precursor protein ATRA All-trans retinoic acid APL Acute promyelocytic leukemia Bax Bcl-2 associated X BH3 Bcl-2 homology 3 Bim Bcl-2-interacting mediator of cell death BimEL Bim-extra long CDK Cyclin-dependent kinase Cellular and Molecular Life Sciences

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“…Indeed, several proteins such as p53, cyclin F, among others, were found to be inversely correlated in NDD with cancer. In addition, several other factors were up- or down-regulated in both diseases, including protein phosphatase 2 (PP2A), cyclins D and E, among others ( Seo and Park, 2019 ). The existence of overlapping regulation of pathogenic molecules involved in both GBM and NDDs, although the underlying mechanisms of regulation could be distinct, raise the possibility that these molecular links may have the relevant potentiality to be exploited for developing prognostic biomarkers and therapeutic strategies.…”

“…There is increasing evidence showing brain cancer and neurodegeneration can mutually influence each other. For example, tumor cells secrete glutamate, which drives neurotoxicity and neuronal death, and promotes tumor-associated neurodegeneration ( Seo and Park, 2019 ). Also, tumor cells can communicate with and regulate microenvironment functioning through several mechanisms, including EVs and signaling molecules.…”

“…In support, several epidemiological studies reported an inverse risk between the development of PD or AD and cancer ( Driver, 2014 ). In molecular terms, both cancer and NDDs share signaling molecules but the underlying mechanisms could be distinct ( Seo and Park, 2019 ): cancers become immortal while neurodegeneration kill cells. Therefore, it has become relevant to investigate the linking signaling molecules identified in GBM that also affect NDDs, to better understand the pathogenesis of these diseases.…”

“…Mechanistically, the increased expression of Tau in IDH mutated gliomas impedes EGFR signaling and the transdifferentiation into the more aggressive mesenchymal subtype. Pin1 is also related to proteostasis, and is downregulated in AD and upregulated in PD and cancer ( Seo and Park, 2019 ). Pin1 is a G1 checkpoint controller that can bind to Tau, enhancing its dephosphorylation, and can also interact with α-synuclein to promote its aggregation ( Seo and Park, 2019 ).…”

“…Pin1 is also related to proteostasis, and is downregulated in AD and upregulated in PD and cancer ( Seo and Park, 2019 ). Pin1 is a G1 checkpoint controller that can bind to Tau, enhancing its dephosphorylation, and can also interact with α-synuclein to promote its aggregation ( Seo and Park, 2019 ). Notably, upregulated proteins in NDDs were found structurally disordered, showing a clear evidence of proteinopathy.…”