Cancer linked to Alzheimer disease but not vascular dementia

Roe, Catherine M.; Fitzpatrick, Annette L.; Xiong, Chengjie; Sieh, Weiva; Kuller, Lewis H.; Miller, J. Philip; Williams, Monique; Kopan, Raphael; Behrens, María I.; Morris, John C.

doi:10.1212/wnl.0b013e3181c91873

Cited by 254 publications

(252 citation statements)

References 29 publications

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“…Recent evidence supports the observation of an inverse link between cancer and Alzheimer disease (13). The authors demonstrated that Alzheimer disease was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of Alzheimer disease suggesting a common mechanism linking both diseases.…”

mentioning

confidence: 61%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

110

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The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

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mentioning

confidence: 61%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

110

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“…Increased risk of cancer seems to be associated with decreased chance of AD and there is a complex mechanism relating to these two diseases. These findings suggest the possibility that cancer can be linked to some neurodegenerative diseases (6). At the present time, the biological action of APP is not well explained in cancer cells.…”

Section: Discussionmentioning

confidence: 83%

Alteration of Alzheimer Amyloid Precursor Protein after Treatment with Carbamazepine in Colon Cancer

Akbarzadeh

Zanjani

Sabetkasaei

et al. 2017

Iran Red Crescent Med J

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Background: Amyloid precursor protein (APP), which is involved in cell proliferation, is observed to be over expressed in human cancer. Thus, it is crucial to investigate its role in cancer and suggest treatment strategies to alter its effects on cell growth. Objectives: The main purpose of this study was to determine APP concentrations in colon cancer SW480 cell line after treatment with histone deacetylase inhibitors (HDACIs), namely valproic acid (VPA) and carbamazepine (CBZ). Methods: In the present experimental study, carried out during the period 2014 -2016 in Iran, 1000000 cells were seeded and incubated in a six-well plate for each sample preparation. The cells were then treated with drugs and APP was evaluated. The concentration of this protein was detected using the enzyme-linked immunosorbent assay (ELISA) method. Results: We found that treatment with CBZ (P < 0.001) and VPA (P < 0.001) reduced the APP levels significantly compared to controls. The APP level reduction by CBZ was 41.6% more than that by VPA. Conclusions:The results of this study suggest that APP reduction by HDACIs can apparently play an important role in the treatment of colon cancer.

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“…High CHO intake, in particular in the form of sugar and other high GI foods, has been linked to modern diseases like metabolic syndrome [11], Alzheimer's disease [12,13], cataract and macula degeneration [14][15][16] and gout [17]. Intriguingly, with the possible exception of Alzheimer's disease [18], the occurrence and prognosis of cancer seems positively associated with both the prevalence of these diseases [19][20][21][22][23][24][25][26][27][28] and the GI and glycemic load (GL) of the diet [29][30][31][32]; this implies a possible role of high CHO intake in cancer as well.…”

Section: Modern Hunter-gatherers' Dietmentioning

confidence: 99%

“…This characteristic is the basis for the wide-spread use of the functional imaging modality positron emission tomography (PET) with the glucose-analogue tracer 18 F-fluoro-2-deoxyD-glucose (FDG) (Figure 1). There are mainly four possible drivers discussed in the literature that cause the metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer cells.…”

Section: Possible Causes For the "Warburg Effect"mentioning

confidence: 99%

Nutrition Support To Patients Undergoing Gastrointestinal Surgery

Coles¹

2013

Clinical Nutrition

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Over the last years, evidence has accumulated suggesting that by systematically reducing the amount of dietary carbohydrates (CHOs) one could suppress, or at least delay, the emergence of cancer, and that proliferation of already existing tumor cells could be slowed down. This hypothesis is supported by the association between modern chronic diseases like the metabolic syndrome and the risk of developing or dying from cancer. CHOs or glucose, to which more complex carbohydrates are ultimately digested, can have direct and indirect effects on tumor cell proliferation: first, contrary to normal cells, most malignant cells depend on steady glucose availability in the blood for their energy and biomass generating demands and are not able to metabolize significant amounts of fatty acids or ketone bodies due to mitochondrial dysfunction. Second, high insulin and insulin-like growth factor (IGF)-1 levels resulting from chronic ingestion of CHO-rich Western diet meals, can directly promote tumor cell proliferation via the insulin/IGF1 signaling pathway. Third, ketone bodies that are elevated when insulin and blood glucose levels are low, have been found to negatively affect proliferation of different malignant cells in vitro or not to be usable by tumor cells for metabolic demands, and a multitude of mouse models have shown antitumorigenic properties of very low CHO ketogenic diets. In addition, many cancer patients exhibit an altered glucose metabolism characterized by insulin resistance and may profit from an increased protein and fat intake. In this review, we address the possible beneficial effects of low CHO diets on cancer prevention and treatment. Emphasis will be placed on the role of insulin and IGF1 signaling in tumorigenesis as well as altered dietary needs of cancer patients.

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Cancer linked to Alzheimer disease but not vascular dementia

Cited by 254 publications

References 29 publications

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Alteration of Alzheimer Amyloid Precursor Protein after Treatment with Carbamazepine in Colon Cancer

Nutrition Support To Patients Undergoing Gastrointestinal Surgery

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