Abstract
The beta-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 APPalpha. 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 down-regulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy.
Highlights
Migrating between 110 and 135 kDa [1, 2]
We demonstrated that SH-SY5Y neuroblastoma cells transfected with APP695 showed an increase in cell proliferation compared with mock-transfected controls [12]
We further focused on the molecular mechanism responsible for the highly specific impairment in the maturation of amyloid precursor protein (APP) and the reduction of secreted sAPP␣ caused by VPA in the cancer cell lines
Summary
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. The predominant route of APP processing consists of successive cleavages by ␣- and ␥-secretases in non-neuronal cells [6, 7]. Several studies showed that APP and its secreted forms promote adhesion, migration, neurite outgrowth, and general growth-promoting properties We further focused on the molecular mechanism responsible for the highly specific impairment in the maturation of APP and the reduction of secreted sAPP␣ caused by VPA in the cancer cell lines. GRP78 is a 78-kDa heat shock protein induced by VPA [25], and it is involved in maturation of APP [26]. The aim of this report was to study the potential impact of APP on prominent gastrointestinal tumor growth and to elucidate the underlying molecular mechanism
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