Amyloid β protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo

Abstract

Amyloid ␤ protein precursor (APP) is a membrane-bound protein ubiquitously expressed in a variety of types of cells. However, its biological functions remain largely uncertain, particularly in non-neural cells and tumors. Our previous studies revealed that a secreted form of APP having a Kunitztype inhibitor domain is a major serine proteinase inhibitor secreted by human colon carcinoma cells. In our study, we used an antisense RNA strategy to selectively inhibit the expression of APP in the human colon carcinoma cell line SW837. A vector capable of expressing an antisense mRNA complementary to 911 bases of the 5 end of APP mRNA was transfected into SW837 cells. After selection, 2 stably transfected antisense clones were obtained in which both the APP protein and mRNA were significantly suppressed. The proliferative potential and colony-forming efficiency of the antisense clones in vitro were markedly suppressed compared with the parent and mock-transfected clones. The addition of the conditioned medium of parent cells or purified secretory APP enabled these antisense effects to be overcome in vitro. The suppressed growth was also observed in vivo when the cells were injected subcutaneously into nude mice. Histologically, formation of tubular structures appeared to be suppressed in the antisense clones in vivo. These observations suggest potentially important roles of APP in cellular proliferation and differentiation of colon carcinoma cells. Key words: amyloid ␤ protein precursor; colon carcinoma cell; antisense; growthAmyloid ␤ protein precursor (APP) is a large precursor protein of ␤-amyloid found in neurite plaques of Alzheimer's disease, and it exists in multiple isoforms as a result of alternative splicing of the 19 exons encoded by the APP gene. 1 With regard to exons, exon 7 encodes for 57 amino acids with considerable homology to a Kunitz-type serine proteinase inhibitor, and the secreted protein containing the inhibitor domain is identical to proteinase nexin-II, which was initially isolated from human fibroblasts by its property of forming complexes with epidermal growth factor-binding protein. 2 APP is a ubiquitous protein and synthesized by most cells throughout the body. 1 However, its biological functions are largely unknown, particularly in non-neural tissues. Previously, we reported that human tumor cell lines consistently secreted highmolecular weight trypsin inhibitors, which were identical to the secreted form of APP (sAPP) with Kunitz domain. 3,4 Indeed, sAPP represented the major trypsin inhibitor produced by a panel of colon carcinoma cell lines. 5 This evidence suggests that APP and/or sAPP may have important, though undefined, biological functions in tumor cells, including colon carcinoma cells.To date, a limited amount of evidence is available for the possible role of APP in non-neural cells and essentially nothing is known about its function in tumors of systemic organs. 1 Saitoh et al. 6 showed that APP can be a potent growth factor for fibroblasts as well as for thyroid follicular e...

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

“…Gain-of-function studies showed that APP overexpression leads to increased cellular proliferation (12,17,42). Lossof-function studies either by APP knockdown (14,16,17) or blockage of sAPP function by antibody application (15) demonstrated regression of carcinoma growth in vitro and in vivo. Such a functional relationship between APP expression and proliferation demonstrates the importance of APP in the pathogenesis of cancer.…”

“…The extracellular domain interacts with matrix proteins and heparan sulfate proteoglycans reflecting its role in migration, adhesion, and cell-matrix and cell-cell interactions (45)(46)(47)(48). Recently, it has been shown that APP is up-regulated in several cancer species, including pancreatic (15), colon (14), melanoma (49), and prostate cancer (17), as well as oral squamous cell carcinoma (15), and has growth-promoting features. Different kinds of stimuli can enhance APP expression.…”

“…We and others have shown that APP overexpression leads to increased proliferation and that APP is pathophysiologically up-regulated in various cancer types (12,14,16,17). On the other side, VPA treatment leads to growth inhibition by pharmacological down-regulation specifically of APP.…”

Increased expression of amyloid precursor protein promotes proliferation and migration of AML1/ETO-positive leukemia cells and be inhibited by panobinostat

“…Recent work have identified that increased expression of APP is assumed to be a promoting factor for malignant tumors. In the human colon carcinoma cell line SW837, inhibition of APP expression using an antisense RNA strategy markedly suppresses proliferative potential and colonyforming efficiency compared with the mock-transfected clones in vitro [18]. A research of APP on prostate cancer indicated that APP promotes the growth of prostate cancer cells, and knockdown of APP in mice represses tumor growth [19].…”

Amyloid precursor protein as a potential marker of malignancy and prognosis in papillary thyroid carcinoma

“…Our results showed that high APP scores significantly correlated with large tumor size, extracapsular invasion, and lymph node metastasis in PTC. Several studies have shown that patients with increased APP levels have a significantly lower survival rate and APP has therefore been suggested as a potential biomarker for the evaluation of cancer prognosis (5,9,10,12). For PTC patients, tumor size, lymph node metastasis and extracapsular invasion are recognized as important prognostic factors (16).…”