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

Abstract

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 ...

ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells

“…ADAM10, A disintegrin and metalloproteinase 10. several critical transmembrane molecules including amyloid precursor protein (28,29). It must be noted that soluble amyloid precursor protein has been related to the growth of several types of cells (30,31), which suggests that ADAM10 may influence the proliferation of HepG2 cells via amyloid precursor protein shedding.…”

Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells

“…Extensive investigation has revealed that ADAM10 cleaves amyloid precursor protein (24,25), a protein associated with the growth of several types of cell (26,27). ADAM10 has also been reported to activate Notch signaling by suppressing the ectodomain shedding of Δ-1, which subsequently results in a marked inhibitory effect on tumor cell proliferation (28).…”

Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

“…The epigenetic influence of HDIs on gene expression make them a useful new class of pharmacological agents that could ameliorate various disease conditions. For example, HDIs also promote neuronal survival in ischemic injury, [14][15][16][17] multiple sclerosis [18,19], and Alzheimer's and Huntington's disease models [20][21][22][23][24]. These multiple roles of HDIs can be attributed to alterations in the expression of different gene sets by increasing acetylation of chromatin.…”