Emerging Evidences for an Implication of the Neurodegeneration-Associated Protein TAU in Cancer

Abstract

Neurodegenerative disorders and cancer may appear unrelated illnesses. Yet, epidemiologic studies indicate an inverse correlation between their respective incidences for specific cancers. Possibly explaining these findings, increasing evidence indicates that common molecular pathways are involved, often in opposite manner, in the pathogenesis of both disease families. Genetic mutations in the MAPT gene encoding for TAU protein cause an inherited form of frontotemporal dementia, a neurodegenerative disorder, but also increase the risk of developing cancer. Assigning TAU at the interface between cancer and neurodegenerative disorders, two major aging-linked disease families, offers a possible clue for the epidemiological observation inversely correlating these human illnesses. In addition, the expression level of TAU is recognized as a prognostic marker for cancer, as well as a modifier of cancer resistance to chemotherapy. Because of its microtubule-binding properties, TAU may interfere with the mechanism of action of taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network and impair cell division. Indeed, a low TAU expression is associated to a better response to taxanes. Although TAU main binding partners are microtubules, TAU is able to relocate to subcellular sites devoid of microtubules and is also able to bind to cancer-linked proteins, suggesting a role of TAU in modulating microtubule-independent cellular pathways associated to oncogenesis. This concept is strengthened by experimental evidence linking TAU to P53 signaling, DNA stability and protection, processes that protect against cancer. This review aims at collecting literature data supporting the association between TAU and cancer. We will first summarize the evidence linking neurodegenerative disorders and cancer, then published data supporting a role of TAU as a modifier of the efficacy of chemotherapies and of the oncogenic process. We will finish by addressing from a mechanistic point of view the role of TAU in de-regulating critical cancer pathways, including the interaction of TAU with cancer-associated proteins.

Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis

“…The protein Tau is a molecule at the crossroads between brain tumors and neurodegenerative diseases [ 17 , 38 ]. Tau accumulation and aberrant phosphorylation is a driver of Alzheimer’s disease, and Tau expression has also been recognized as a prognosis or predictive marker for chemotherapeutic response in several cancers [ 11 , 17 , 39 ]. In the present work, by down-regulating Tau expression in glioblastoma U87-MG cells, we show that Tau contributes to tumor progression in vivo and in vitro.…”

“…In the present work, by down-regulating Tau expression in glioblastoma U87-MG cells, we show that Tau contributes to tumor progression in vivo and in vitro. Available published results suggest that the function of Tau in cancer is dependent on tumor/cell type [ 17 ]. Previous work has shown that MAPT gene expression is enriched in LGGs as compared to GBMs [ 19 , 40 ].…”

“…It has been shown that the risk of developing cancer is significantly higher in families affected by genetic tauopathies proposing that Tau may be a risk factor for cancer [ 14 ]. A correlation between Tau expression and poor disease outcome has been proposed in ovarian, prostate and colorectal cancer [ 15 , 16 , 17 ]. On the other hand, high levels of Tau expression have been positively correlated with better patient survival, independently of the therapy in breast cancer and low-grade gliomas (LGG) [ 18 , 19 ].…”

Tau and stathmin proteins in breast cancer: A potential therapeutic target

“…This allows tau to perform several tasks. Because it will enable cell‐cycle progression while also creating a milieu for cancer cell proliferation aided by tau protein, the microtubule structure is critical during mitotic division 36 …”

p53 Knock Out Mice Enhances Anxiety- and Depression-Like Behaviors through an Increase of Glutamate, Calcium, and Cytokine-Mediated Cell Death Signals

“…A transcriptomic meta-analysis of three ND types and three cancer types (lung, prostate, and colorectal) demonstrated the inverse comorbidities, and signi cant overlapping genes were found to be upregulated in NDs but downregulated in cancers. They were also found to be downregulated in NDs but upregulated in cancers [2][3][4][5] . One of these molecules, p53, is potentially responsible for regulating the development of NDs and cancer [6][7][8] .…”