Exploiting APC Function As a Novel Cancer Therapy
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Send Orders for Reprints to [email protected] 90 Current Drug Targets, 2014, 15, 90-102 Exploiting APC Function as a Novel Cancer Therapy Alyssa C. Lesko1, Kathleen H. Goss2 and Jenifer R. Prosperi1,3,* 1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, 2Department of Surgery, University of Chicago, Chicago, IL 60637, 3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, IN 46617, USA Abstract: The Adenomatous Polyposis Coli (APC) tumor suppressor is most commonly mutated in colorectal cancers such as familial adenomatous polyposis (FAP); as well as many other epithelial cancers like breast, pancreatic, and lung cancer. APC mutations usually result in a truncated form of the protein lacking the carboxy-terminal region resulting in loss of function. Mutations in APC have been identified in early stages of cancer development making it a gatekeeper of tumor progression and therefore an ideal therapeutic target. APC is best known for its role as a negative regulator of the Wnt/ -catenin pathway. However, APC also mediates several other normal cell functions independently of Wnt/-catenin signaling such as apical-basal polarity, microtubule networks, cell cycle, DNA replication and repair, apoptosis, and cell migration. Given the vast cellular processes involving APC, the loss of these “normal” functions due to mutation can con- tribute to chemotherapeutic resistance. Several therapeutic treatments have been explored to restore APC function includ- ing the reintroduction of APC into mutant cells, inhibiting pathways activated by the loss of APC, and targeting APC- mutant cells for apoptosis. This review will discuss the normal functions of APC as they relate to potential treatments for patients, the role of APC loss in several types of epithelial cancers, and an overview of therapeutic options targeting both the Wnt-dependent and -independent functions of APC. Keywords: APC, cancer, targeted therapy, tumor suppressor INTRODUCTION of APC as they relate to potential treatments for patients with APC-mutant tumors, will discuss the importance of APC in a Mutations in the Adenomatous Polyposis Coli (APC) tu- variety of epithelial-derived tumors, and finally will investi- mor suppressor gene are most commonly found in colorectal gate options for restoring APC function and therefore treat- cancers such as the inherited syndrome familial adenomatous ing APC-mutant tumors. polyposis (FAP), but have also been identified in many epithelial cancers including breast cancer ([1-3] and re- NORMAL FUNCTIONS OF THE APC TUMOR SUP- viewed in [4]). Most APC mutations are nonsense mutations, PRESSOR frequently created by frame-shifts, resulting in premature stop codons and a truncated gene product lacking the car- APC (by convention, the human and mouse genes are boxy-terminus of the protein. Patients with FAP inherit one APC and Apc, respectively, whereas the protein from all spe- germline mutation and develop tumors when another somatic cies is APC) is a large multifunctional protein made up of mutation is received resulting in loss of the wild-type APC 2843 amino acids and multiple binding domains. While the allele. In this way, APC mutation follows the classical ‘two- best-known role of APC is to act as a negative regulator of hit’ model. The disease presentation in patients with APC the Wnt/-catenin signaling pathway, there are many other mutation often depends on the location of the mutation. For normal functions of APC. Based on the ability of APC to example, mutations at the 5’ and 3’ ends of the coding se- bind a variety of protein partners, other activities of APC quence are associated with a weakened FAP phenotype, include mediating cell migration, regulation of apical-basal while extracolonic phenotypes are associated with mutations polarity, microtubule networks, cell cycle, DNA replication in other regions of the sequence ([5] and reviewed in [6]). and repair, and apoptosis (summarized in Fig. 1). These Importantly, APC mutations similar to those found in FAP functions of APC, including regulation of Wnt/-catenin have been identified in 50-80% of sporadic colon adenomas signaling and other non-Wnt related functions have been and adenocarcinomas (reviewed in [4, 7]). Since APC has recently reviewed elsewhere [9, 10]. Prior to discussion of been identified in the earliest stages of tumor progression targeting APC loss in cancer therapeutics, we will briefly [8], it has emerged as the ‘gatekeeper’ of colorectal cancer summarize some key functions of APC that may be targeted development. This review will describe the normal functions in cancer. Association of APC with Polarity and Junctional Com- *Address correspondence to this author at the Department of Biochemistry plexes and Molecular Biology, Indiana University School of Medicine – South Bend, 1234 Notre Dame Ave, South Bend, IN 46617, USA; Role in Apical-Basal Polarity of Epithelial Cells: Some Tel.: 574-631-4002; Fax: 574-631-8932; Email: [email protected] non-gastrointestinal model systems have provided evidence 1873-5592/14 $58.00+.00 © 2014 Bentham Science Publishers Exploiting APC Function as a Novel Cancer Therapy Current Drug Targets, 2014, Vol. 15, No. 1 91 Fig. (1). APC protein structure. Specific APC functional domains are shown, and known binding partners are listed below the domain with which they interact. for the involvement of APC in regulating aspects of apical- uted to this function; however, the loss of epithelial polarity basal polarity and epithelial morphogenesis. For example, a and the disruption of tissue organization are normally associ- role for APC in overall epithelial organization is supported ated with more aggressive cancers ([19, 20] for review). by the homozygous germline deletion of Apc preventing de- Moreover, disrupted localization of adherens junction pro- velopment past embryonic day 6 [11]. Apc mutations in the teins is frequent in cancers [21], and components of the mature cochlea result in a decreased number of parallel mi- Scrib/Dlg/Lgl complex, protein partners of APC, have re- crotubule arrays, which are essential for epithelial polariza- cently been implicated in several cancers such as cervical tion [12]. Studies from our laboratory have also demon- and colorectal cancer [20, 22, 23]. Collectively, these data strated a role for APC in mammary epithelial cell polariza- support a role for APC in epithelial polarization that may be tion and morphogenesis as ApcMin/+ female mice, containing important for its function during tumor development. a mutant Apc allele, exhibited altered mammary epithelial Junctional Complexes: A potential role of APC in medi- polarity and overall integrity [13]. In addition, knockdown of ating cell-cell interactions and cell migration emerged APC in the Madin-Darby Canine Kidney (MDCK) model, a through the interaction of APC with -catenin at the adher- standard model for epithelial polarity, resulted in altered ens junction [24], and plakoglobin (-catenin), at the desmo- epithelial morphogenesis and polarity defects in 3D culture some [25, 26]. However, the APC/-catenin and - (J.R.P and K.H.G., submitted). In Drosophila neuroepithelial catenin/E-cadherin complexes were observed to be mutually cells, APC is recruited to the adherens junction, and mediates exclusive [24, 26, 27], and studies have largely focused on symmetric cell division along the planar axis through its in- APC’s regulation of the Wnt pathway through -catenin deg- teractions with microtubules by positioning the mitotic spin- radation. Although the role of APC in cellular adhesion, mo- dle [14]. Other roles for APC include the polarized distribu- tility, polarization, and morphogenesis has been overshad- tion of MUC1, a transmembrane glycoprotein that is fre- owed, there is evidence that unregulated APC levels are as- quently mislocalized in cancers, to the apical membrane of sociated with altered cell migration and adhesion. Manipula- differentiated mammary epithelial cells [13], and the binding tion of APC levels in mouse intestinal epithelial cells re- of APC to Striatin, a calmodulin-binding protein predomi- sulted in altered enterocyte migration along intestinal villi in nately expressed in the central nervous system, in cell-cell vivo [28-30]. Reintroduction of APC in SW480 (APC- junctions [15]. mutant) colorectal cancer cells caused changes in the local- The role of APC in maintaining apical-basal polarity is ization of adherens junction proteins, tighter cell-cell con- also conveyed in it’s importance in epithelial cell differentia- tacts, and an epithelial phenotype [31]. Localization of APC tion, as the establishment of polarity is required for differen- at cell-cell contacts has been shown to be dependent on - tiation. APC’s role in zebrafish intestinal differentiation in- catenin and VE-cadherin, as depletion of either -catenin or volves the transcriptional co-repressor carboxy-terminal VE-cadherin resulted in the disruption of cell-cell adhesion binding protein 1 (CtBP1), which interacts with APC to and the loss of APC from the lateral membrane [32]. Studies drive differentiation independent of -catenin through con- using wound healing assays also showed that the inhibition trolling the expression of enzymes like intestinal retinal de- of glycogen synthase kinase 3 (GSK3) and casein kinase I hydrogenases [16, 17]. A recent study showed that APC is (CK1) decreased wound closure, suggesting that cell mi- also required for apical extrusion of human