. Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010 Apr 2;285(14):10678-89. PubMed.

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  1. Although having been extensively studied for over 20 years, the physiological function of APP still remains largely unknown. In this paper, the authors provide evidence showing that APP is involved in the growth control of pancreatic and colon cancers.

    APP can be cleaved by various proteases (α-, β-, and γ-secretases) to generate different metabolites. One of them, Aβ, is well known for its neurotoxicity and involvement in the pathogenesis of Alzheimer disease (AD). In contrast, another common APP proteolytic product of the α-secretase cleavage, sAPPα, has been demonstrated by our group, as well as others, to be neuroprotective. Our previous study (Han et al., 2005) found that sAPPα can prevent excitotoxicity/apoptosis by suppressing Cdk5 overactivation and tau hyperphosphorylation. Recently, we also found that sAPPα is involved in statins’ excitoprotection and can block calpain activation (Ma et al., 2009). Consistent with this protective effect of sAPPα, in this JBC paper, the authors found that APP is abundant in pancreatic adenocarcinoma and colon cancer tissue. Valproic acid (VPA), a histone deacetylase inhibitor used for epilepsy and bipolar disorder treatments, can cause APP downregulation and reduced growth/survival of such cancer cells, the latter of which can be rescued by sAPPα.

    An inverse correlation between AD and cancer incidence has been observed. Our recent study (Zhang et al., 2007), as well as others (Li et al., 2007), showed that mice deficient in PS1/γ-secretase activity have an upregulated EGFR level and increased skin tumorigenesis. Further mechanistic studies revealed that APP intracellular domain (AICD), released by γ-secretase cleavage of APP, has transactivation activity and can negatively regulate expression of the EGFR gene, whereas sAPPα does not affect EGFR level. These results suggest that AICD controls cell growth/survival through modulating EGFR and provides a molecular link between AD and cancers. Indeed, overexpression of APP/AICD has been found to induce apoptosis in certain cells. Interestingly, in this JBC paper, the authors suggest that it is sAPPα that modulates the growth/survival of pancreatic and colon cancer cells, whereas a reduction of APP level (which should be accompanied by a reduction of AICD level) by VPA treatment did not affect EGFR level. The discrepancy between these studies could be explained by differences in cleavage preference for APP in various cell types. Therefore, APP may be subjected to β- and γ-cleavage for pro-death factors (Aβ and AICD) in certain cells but subjected to α-cleavage for pro-survival factors (sAPPα) in other cells, with the observed physiological function of APP in these cells decided by its dominant metabolic product.

    References:

    . Suppression of cyclin-dependent kinase 5 activation by amyloid precursor protein: a novel excitoprotective mechanism involving modulation of tau phosphorylation. J Neurosci. 2005 Dec 14;25(50):11542-52. PubMed.

    . Statin's excitoprotection is mediated by sAPP and the subsequent attenuation of calpain-induced truncation events, likely via rho-ROCK signaling. J Neurosci. 2009 Sep 9;29(36):11226-36. PubMed.

    . Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10613-8. PubMed.

    . Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase. J Biol Chem. 2007 Nov 2;282(44):32264-73. Epub 2007 Sep 7 PubMed.

  2. The study by Venkataramani et al., 2010 (1), supports findings from previous reports that implicate the β amyloid precursor protein (APP) as a crucial intermediate in the control of pancreatic and colon cancer cell growth. Interestingly, the amino terminal RERMS sequence of a secreted form of APP (sAPP) is shown to be required for this biological activity. Moreover, valproic acid (VPA), a well-known antiepileptic drug, prevents the growth-promoting effect of APP, and the study links this ability of VPA to its activity as a histone deacetylase (HDAC) inhibitor. Finally, the authors show that VPA-mediated HDAC inhibition increases GRP78 (also known as the ER chaperone BiP) expression, and suggest that binding of GRP78 to immature forms of APP blocks ER to cis-Golgi translocation, hence processing and maturation of APP to generate sAPPα.

    APP is a ubiquitous, single transmembrane protein with a receptor-like structure best known for its key role in the pathogenesis of Alzheimer disease (2). It can be differentially processed by secretases via either the amyloidogenic or non-amyloidogenic pathway. In the first case, consecutive processing by β-secretase and then γ-secretase generates the β amyloid peptide (Aβ), present in Alzheimer senile plaques, in addition to an extracellular soluble βAPP peptide (sAPPβ) and a small intracellular peptide (AICD). On the other hand, the non-amyloidogenic pathway involves α-secretase and then γ-secretase processing to generate a smaller non-amyloidogenic peptide (p3), a larger soluble extracellular APP fragment (sAPPα), and AICD. In non-neuronal cells, APP is predominantly processed via the non-amyloidogenic route (3,4). Alternatively, in Alzheimer disease, Aβ accumulation is prevalent, suggesting that the amyloidogenic pathway is amplified in this disorder. The relevance of Aβ and APP in AD is further supported by genetic evidence available for familial forms of AD where the presence of mutations in genes encoding APP and presenilin, a component of γ-secretase, was detected (5).

    Previous studies have shown that the soluble sAPPα fragment released to the extracellular space has growth factor-like properties in neuronal and non-neuronal cells (6-10), as well as in progenitor cells in the adult subventricular zone (11). Interestingly, several reports uncovered a potential link between APP and cancer, since APP overexpression was associated with increased proliferation of prostate, colon, pancreas, oral squamous carcinoma, and melanoma cells. Also, increased APP levels correlated with significantly lower patient survival rates, highlighting the potential of APP as a biomarker for cancer prognosis (12-16). Venkataramani et al. (1) now add evidence to this line of thinking by documenting, in immunohistochemical studies, the abundant presence of APP in human pancreatic adenocarcinoma and colon carcinoma, but not in healthy tissue samples, as well as showing that APP knockdown, using an siRNA approach, reduces the proliferation of human pancreatic and colon cancer cell lines. These results point towards APP as a potentially important player in tissue repair and cancer.

    We have previously reported on the existence of an inverse relationship between cancer and AD. In longitudinal studies (17,18), the presence of one disease was found to correlate with a reduced probability of subsequently diagnosing the other. This association was observed for dementia of the Alzheimer’s type, but not for vascular dementia, suggesting the existence of a common biological mechanism underlying neurodegenerative disorders and cancer (19). Cancer is associated with enhanced growth of specific cell populations through alterations in mechanisms that control cell cycle progression and reduce susceptibility to apoptotic stimuli. In degenerative disorders like AD, on the other hand, cell death is augmented. Therefore, deregulation, in the opposite sense, of a fundamental biological process, like apoptosis, may participate in the genesis of both diseases.

    Bearing this in mind, it is intriguing to postulate that, at the molecular level, APP cleavage via different secretase-mediated routes may provide the sought-after link between cancer and AD. Indeed, proteolysis of APP via the amyloidogenic and non-amyloidogenic pathways is known to be reciprocal, in that impaired α-secretase-mediated proteolysis enhances processing by the amyloidogenic β-secretase (20). Furthermore, following this line of thought, one could speculate that APP processing to generate mainly sAPPα may promote cell growth, whereas prevalence of the sAPPβ-generating route would have a growth inhibitory or degenerative effect. Evidence in favor of this idea is indeed available. For instance, incubation with Aβ inhibits the proliferation of a variety of cancer cell lines (21). Additionally, a recent study shows that sAPPβ can bind the death receptor, DR6, and promote neurodegeneration (22). Alternatively, studies including the one by Venkataramani et al. (1) confirm the notion that sAPPα enhances viability and proliferation of cancer cells.

    In summary, based on the recent findings by Venkataramani et al. (1), and the evidence cited from the literature, one is tempted to propose that individuals with an imbalance in amyloidogenic versus non-amyloidogenic APP processing that is skewed towards the amyloidogenic branch should have a higher propensity to develop AD, but be protected from cancer, whereas those with augmented non-amyloidogenic processing should be protected from AD but have an elevated tendency to develop cancer. If so, studies like the one by Venkataramani et al. (1), identifying inhibitors that alter APP processing, are likely to become an extremely exciting area of research, given that they have potential to yield effective treatments for both of these devastating human diseases. Interestingly, VPA has been reported as a promising agent to treat AD (23).

    References:

    . Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010 Apr 2;285(14):10678-89. PubMed.

    . Biochemistry and molecular biology of amyloid beta-protein and the mechanism of Alzheimer's disease. Handb Clin Neurol. 2008;89:245-60. PubMed.

    . Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6075-9. PubMed.

    . A closer look at alpha-secretase. Curr Alzheimer Res. 2008 Apr;5(2):179-86. PubMed.

    . Recent insights into the molecular genetics of dementia. Trends Neurosci. 2009 Aug;32(8):451-61. PubMed.

    . Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts. Cell. 1989 Aug 25;58(4):615-22. PubMed.

    . Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12683-8. PubMed.

    . Altered cholesterol metabolism in APP695-transfected neuroblastoma cells. Brain Res. 2007 Jun 4;1152:209-14. PubMed.

    . Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7450-4. PubMed.

    . From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1770-5. PubMed.

    . Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development. 2004 May;131(9):2173-81. PubMed.

    . Amyloid beta protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer. 2001 Apr 1;92(1):31-9. PubMed.

    . Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res. 2003 Nov 1;63(21):7032-7. PubMed.

    . Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer. 2004 Sep 20;111(5):727-32. PubMed.

    . Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res. 2009 Jan 1;69(1):137-42. PubMed.

    . Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein. J Invest Dermatol. 2010 May;130(5):1400-10. PubMed.

    . Alzheimer disease and cancer. Neurology. 2005 Mar 8;64(5):895-8. PubMed.

    . Cancer linked to Alzheimer disease but not vascular dementia. Neurology. 2010 Jan 12;74(2):106-12. PubMed.

    . A common biological mechanism in cancer and Alzheimer's disease?. Curr Alzheimer Res. 2009 Jun;6(3):196-204. PubMed.

    . A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004 May;113(10):1456-64. PubMed.

    . Bioluminescence imaging reveals inhibition of tumor cell proliferation by Alzheimer's amyloid beta protein. Cancer Cell Int. 2009;9:15. PubMed.

    . APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PubMed.

    . Valproic acid as a promising agent to combat Alzheimer's disease. Brain Res Bull. 2010 Jan 15;81(1):3-6. PubMed.

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