**3. Tau in cancer**

Tau expression has also been noticed in different non-neuronal cells like those of the liver, kidney, muscle and so on [126, 127] Tau protein has also been expressed in human breast, prostate, gastric and pancreatic cancer cell lines and tissues [12–16]. Tau is also found in patients with twisted tubulofilaments of inclusion-body myositis [19].

As both cancer and AD are age-related diseases, and as both diseases occur mainly in developed countries with similar dietary habits, there might be some correlation between the two diseases. Additionally, tau-positive and tau-negative cancer cells show different results after treatment with chemotherapeutic agents like paclitaxel [14].

In case of breast cancer, 52% patients are tau negative [14]. An approximately same result (57%) of tau expression in breast cancer was found in a research by a different group [128]. There are a lot of experiments based on breast cancer that show different percentages of tau negative. In case of gastric cancer, 30% patients are tau negative [15], whereas 25.7% patients are tau negative in case of ovarian cancer [25]. These results suggest that tau protein expression may be diverse for different cancer sites. The causes of different cell lines expressed as tau positive or negative are not clear enough. In case of prostate cancer, androgen-independent prostate lines show a considerably higher level of tau than androgen-dependent cells lines. Even androgenindependent derivative cell line isolated from androgen-dependent line shows higher amount of tau than that of the original cells. Also, in case of ovarian cancer cells, endometrioid carcinoma cell types express higher levels of tau protein compared to other cells. Estrogen also regulates tau protein expression [129]. A more extensive analysis will be required to confirm all of these causes of tau expression level of different cell lines.

mainly in neuronal cells and in glial cells, such as prickle-shaped astrocytes and twisted bodies [121]. Like PSP, Pick's disease is also associated with a mutation in the tau gene. However, Pick's disease is not a distinct entity but one of the subtypes of the variety of diseases associ-

Frontotemporal dementia with Parkinsonism associated with chromosome 17 (FTDP-17) is a neurological disorder that is a part of frontotemporal dementia, categorized by a damage of the neuron in the frontal and temporal lobes of the brain. A loss of these cells can affect personality, behavior, speech and cause motor disturbances. Mutations in the tau gene can cause this dementia. 32 tau gene mutations have been recognized in over 100 families of this syndrome [123]. Tau gene mutations associated with FTDP-17 cause anomalous filament development and an amassing of tau in neuronal and glial cells in the cerebral cortex and in the nuclei of subcortical cells. Tau mutations alter tau isoforms in FTDP-17. The mechanisms

Corticobasal degeneration (CBD) is an adult variable dementia and neurodegenerative syndrome. This is a sporadic disease accounting for one per million cases of dementia per year; the incidence of CBD is ten times lesser than that of Parkinson's disease [124]. In case of CBD, filamentous inclusions in neurons and glia having selective accumulation of hyperphosphorylated four microtubule-binding repeat tau (4R-tau) are seen [125]. The tau H1 MAPT haplo-

Tau expression has also been noticed in different non-neuronal cells like those of the liver, kidney, muscle and so on [126, 127] Tau protein has also been expressed in human breast, prostate, gastric and pancreatic cancer cell lines and tissues [12–16]. Tau is also found in patients

As both cancer and AD are age-related diseases, and as both diseases occur mainly in developed countries with similar dietary habits, there might be some correlation between the two diseases. Additionally, tau-positive and tau-negative cancer cells show different results after

In case of breast cancer, 52% patients are tau negative [14]. An approximately same result (57%) of tau expression in breast cancer was found in a research by a different group [128]. There are a lot of experiments based on breast cancer that show different percentages of tau negative. In case of gastric cancer, 30% patients are tau negative [15], whereas 25.7% patients are tau negative in case of ovarian cancer [25]. These results suggest that tau protein expression may be diverse for different cancer sites. The causes of different cell lines expressed as tau positive or negative are not clear enough. In case of prostate cancer, androgen-independent prostate lines

*2.2.4. Frontotemporal dementia with Parkinsonism associated with chromosome 17 (FTDP-17)*

of the modifications that lead to neuronal death are yet to be discovered.

type is also stalwartly related with CBD pathology, just as it is with PSP [120].

with twisted tubulofilaments of inclusion-body myositis [19].

treatment with chemotherapeutic agents like paclitaxel [14].

ated with temporal dementia [122].

102 Cognitive Disorders

*2.2.5. Corticobasal degeneration*

**3. Tau in cancer**

Tau escalates the deceiving and reconnection of isolated breast tumor cells, and circulatory tumor cells might be responsible for increased risk of disease repetition. That is why the pathological assessment of tau may be useful for patients by diminishing metastasis through circulatory tumor cells mobilization [130].

Heat shock protein (Hsp90) inhibitors are used as possible cancer treatment agents as several cancer-related proteins become stable by cooperating with Hsp90. Numerous Hsp90 inhibitors reduced tau phosphorylation at different sites of phosphorylation in cells overexpressing mutated human tau [131–134].

Pin1 (peptidyl-prolyl cis/trans isomerase (PPIase)) bonds to phosphorylated tau on the Thr231-pro site and catalyzes the isomerization of pSer/Thr-pro motifs, to prompt conformational changes in tau. These changes keep back the ability of phosphorylated tau to bind microtubules and inspire microtubule-binding abilities, thereby dephosphorylating tau protein via its phosphatase, the protein phosphatase 2 (PP2A) [135]. It is noteworthy that Pin1 is overexpressed in various types of human cancers and is also an outstanding prognostic marker in different cancers [136–138]. Pin1 is a molecular target for cancer therapeutics, as its inhibition in cancer cells can elicit apoptosis and conquer the renovated phenotype [139–141].

The deficiency of active Pin1 is responsible for unusual tau accumulation whereas Pin1 controls cell cycle and is essential for cell division. Pin1 overexpression increases oncogenesis by different cell signaling pathways. There might have been an antithetical association between tauopathies and cancer explained by Pin1 [142].

Many proline-directed protein kinases, such as cyclin-dependent kinases (CDKs), mitogenactivated protein kinase (MAPKs), glycogen synthesis kinases (GSKs) and PP2A, govern the reversible phosphorylation of tau [143–145].

Tau has some roles in signal transduction. There is a high volume of proline residues found in different domains of tau [146] that can interrelate with Src homology 3 (SH3) domain [147]. Tau can also interrelate with the SH3 domain of Src, Fyn and Lck, as revealed by the Glutathione S-transferase (GST) fusion binding assay [148]. The bonding of tau to microtubules has a significant effect on the tau-Fyn interactions, as observed by the biochemical analysis of tau-Fyn binding affinity [149]. Tau could encourage the activity of Src family kinases to measure tau's binding affinity for microtubules, thus resulting in tyrosine phosphorylation. In taxol-stabilized microtubules, Fyn can perform tyrosine phosphorylation without tau; phosphorylation of tubulin increases drastically if tau is added [150]. Hence, the relationship between tau and non-microtubule proteins might have a possibly noteworthy functional significance.

Initially, tau was isolated from the brain, but shortly after that, tau availability was not limited to neurons. In one of the initial experiments, non-neuronal tau from both primary human monocytes and U297 lymphoma cells were studied, and both total and phosphor-specific tau were observed [151]. Several other experiments also exposed the availability of tau in different cell lines and tissues. Some of those experiments were very brief and only a northern or western blot was done to show the availability of tau mRNA or protein, respectively, from the liver and kidney of mice and other tissues of rats [126, 127]. Some of the experiments detected multiple tau isoforms and pointed out the correspondence between non-neuronal tau and neuronal tau [152], whereas others showed the microtubule-binding properties of tau from hepatoma and fibroblast cells [153]. From these experiments, it is clear that tau from both neuronal and non-neuronal cells might show similar properties. In one experiment using several human cell types including HeLa cells, lymphocytes and non-transformed skin fibroblasts, tau was not only observed in the nucleoli of nondividing cells but also observed in higher amounts in the nuclei of cancerous cells that specified a precise protagonist of tau in dividing cells [11]. Hence, tau might have some important functions in fast-dividing cells, which might have an effect on cancer.

Overexpression of Pin1, which is responsible for some types of cancer, works together with tau in a phosphorylation-dependent way to carry out tau phosphorylation at Thr231 [159]. Brains of patients with AD comprise less Pin1 than aged-matched normal brains; hyperphosphorylation of tau, behavioral defects as well as other forms of neurodegeneration might have occurred, owing to the loss of Pin1 [160]. When one copy of the p73 gene, a p53 family member that regulates Pin1 [161], was missing, thus leaving only one efficient copy, age-related neurodegeneration and tau hyperphosphorylation were induced [162]. Although tau influ-

Tau in Tauopathies That Leads to Cognitive Disorders and in Cancer

http://dx.doi.org/10.5772/intechopen.74025

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Two important properties of cancer, cell signaling pathway and cell cycle progression, can be modulated by tau. As both AD and most cancers are primarily observed in aged populations,

Patients with AD have a lower risk of different cancers. The genes that are overexpressed in AD and Parkinson's disease-type CNS diseases were downregulated in different cancers like

Folic acid (also called folate or vitamin B9) intensities can plummet due to the influence of certain chemotherapy drugs used for cancer treatment. Chemotherapy-initiated folic acid insufficiency prompts abnormal tau phosphorylation, which can lead to different tauopathies

Paclitaxel is one of the most important chemotherapy drugs for cancer treatment; it binds to beta-tubulin in the same place as tau protein. Cancer cells with a low tau expression show a higher sensitivity to paclitaxel, whereas those with a high expression of tau display a resistance to paclitaxel-related chemotherapy. In case of breast cancer, low tau expressions are

Tau-negative expression can be used to select gastric cancer patients for paclitaxel treatment, on the basis whether paclitaxel is more functional in cells with low or no tau expression [165]. Tau expression analysis should be considered for taxane-based chemotherapy for some types of bladder cancer, as tumors with low tau expression display an enhanced response to chemotherapy [166]. Tau expression is associated with the sensitivity of breast cancer cells to taxanebased chemotherapy; patients with low or no tau expression should be more responsive to chemotherapy than patients with high expression of tau [24, 167]. Tau expression is also a potential marker for response to chemotherapy and subsequent survival in lung, ovarian,

Nowadays, some drugs used for the treatment of cancer are also used for the treatment of different neurological disorders like Parkinson's disease and AD. Nilotinib is an FDA-approved protein tyrosine kinase inhibitor (TKI), which is used for the treatment of chronic myeloid leukemia. It also targets AD, which produces neuroinflammation and misfolded proteins, to ultimately reduce cognitive damage. In Parkinson's disease, nilotinib triggers autophagy to remove hyperphosphorylated tau from the brain before they accumulate as plaques [168, 169].

ences neuronal death, its mechanism for doing so is not clear.

the role of tau in cancer cells may be linked with tauopathies.

favorable for paclitaxel administration during chemotherapy.

lung, colon and prostate cancer and vice versa [163].

**4. Tau in chemotherapy**

pancreatic and prostate cancer.

like AD [164].

Tau might work as a possible modulator of drug resistance. Microtubule-targeting drug estramustine-resistant [154] E4 cells expressed a massive amount of tau at both the mRNA and the protein levels, unlike DU145 cells [13]. This experiment exposed significance of the incidence of tau in non-neuronal cells; this might have a connection with signal transduction and tau's microtubule-binding properties. The expression of tau is considerably diverse in cases of residual disease or in those with a pathological complete response (pCR) in patients with breast cancer undergoing chemotherapy by the microtubule-depolymerizing drug, paclitaxel. The residual disease group expressed more tau than the pCR group [14]. siRNA knockdown tau is more vulnerable to paclitaxel treatment than the wild-type tau in case of breast cancer cells [14, 26]. A nearly similar report was published, about the relationship between tau and paclitaxel resistance in case of gastric cancer [15].

As hyperphosphorylation of tau leads to AD, and tumor suppressor pRB protein as well as different cell cycle activators like Cdk4, Cdk2, cyclin D, cyclin B and PCNA are also present in the neurons of patients with AD, there might be an insinuation of the re-commencement of the cell cycle, which could be a mechanism of neurodegeneration [20]. In case of other neurodegenerative disorders that might be caused by tau protein including FTDP-17, PSP and CBD, these cell cycle activators were found [155]. Tau phosphorylation occurred at disease-relevant sites of primary rat neurons after insertion of oncogenes [156]. This is suggested by the fact that abnormal tau-related diseases are linked to cell cycle markers in several diseases, including cancer. The aged control mouse does not express the increase of the cell cycle marker, PCNA and cyclin D; this was responsible for the sign of neurodegeneration [157]. For normal human tau-expressing transgenic mice, increased tau phosphorylation occurred, along with insoluble tau being found in the brains of aged mice [157]. This suggests that irregular cell cycle re-entry might explain the presence of tau. CNS tissue from the *Drosophila* model used to study neurodegenerative diseases exhibited an increase in the cell cycle markers, PCNA and phosphor-histone 3, as well as neuronal loss [158], which is also evidence that tau drives cell cycle re-entry. The visible neuronal loss in *Drosophila* for either wild-type or mutant tau was overturned by hindering the mammalian target-of-rapamycin (mTOR) pathway, as well as by obstructing the cell cycle in different ways [158]. This finding also links cell signaling with tau-activated neurodegeneration. There are further associations between AD and cancer, as high levels of cancer-related proteins like Fos, Jun and BRCA1 are found in AD [21, 22]. Overexpression of Pin1, which is responsible for some types of cancer, works together with tau in a phosphorylation-dependent way to carry out tau phosphorylation at Thr231 [159]. Brains of patients with AD comprise less Pin1 than aged-matched normal brains; hyperphosphorylation of tau, behavioral defects as well as other forms of neurodegeneration might have occurred, owing to the loss of Pin1 [160]. When one copy of the p73 gene, a p53 family member that regulates Pin1 [161], was missing, thus leaving only one efficient copy, age-related neurodegeneration and tau hyperphosphorylation were induced [162]. Although tau influences neuronal death, its mechanism for doing so is not clear.

Two important properties of cancer, cell signaling pathway and cell cycle progression, can be modulated by tau. As both AD and most cancers are primarily observed in aged populations, the role of tau in cancer cells may be linked with tauopathies.

Patients with AD have a lower risk of different cancers. The genes that are overexpressed in AD and Parkinson's disease-type CNS diseases were downregulated in different cancers like lung, colon and prostate cancer and vice versa [163].
