Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer

Abstract

Adenomatous polyposis coli (APC) is widely accepted as a tumor suppressor gene highly mutated in colorectal cancers (CRC). Mutation and inactivation of this gene is a key and early event almost uniquely observed in colorectal tumorigenesis. Alterations in the APC gene generate truncated gene products, leading to activation of the Wnt signaling pathway and deregulation of multiple other cellular processes. It has been a mystery why most patients with CRC retain a truncated APC protein, but accumulating evidence suggest that these C terminally truncated APC proteins may have gain of function properties beyond the well-established loss of tumor suppressive function. Here, we will review the evidence for both the loss of function and the gain of function of APC truncations and how together they contribute to CRC initiation and progression.

Figure 1.

Structure and major functions of full length and truncated APC. A) Full length APC proteins contain multiple domains including oligomerization domain, an armadillo repeat-domain, a 15- or 20-residue repeat domain important for binding to β-catenin, SAMP repeats for axin binding, a basic domain for microtubule binding, and C-terminal domains that bind to EB1 protein. Due to its numerous interactions with a variety of proteins, APC is involved in cellular processes related to cell migration, adhesion, proliferation, differentiation, and chromosomal segregation. Most of APC mutations occur within mutation cluster region (MCR). B) The C-terminally truncated proteins present in CRC lack the domains that are required for binding to microtubule, EB1 and β-catenin, thus leading to the induction of chromosomal instability, activation of proliferation, and inhibition of differentiation. Truncated APC may have dominant properties that lead to stronger stimulation of cell migration and promotion of cellular survival.

Figure 2.

Lollipop plot showing the distribution and classes of mutations in APC across colorectal cancer datasets in The Cancer Genome Atlas. Plot originally generated using the cBioPortal (103). Light circles indicate missense mutations and dark circles indicate truncating mutations (including nonsense, nonstop (mutation occurring within a stop codon), frameshift deletion, frameshift insertion and splice site mutations). Arm=armadillo.

Figure 3.

Multiple roles of APC truncations in colorectal tumorigenesis. Both the loss of tumor suppressive functions and gain of functions of truncated APC proteins contribute to the initiation, progression and maintenance of colorectal cancer. BER=base excision repair; DSB=double stranded break.

Figure 4.

Dependency of colorectal cancer (CRC) cells on truncated APC for cell growth and survival. In early stage of CRC tumorigenesis, APC truncations can promote tumorigenic properties in the presence of other genetic alterations. Gradually, the late stage CRC cells with altered signaling network become “addicted” to truncated APC for cell survival and maintaining tumorigenic properties. Interfering with expression/functions of truncated APC can affect cellular proliferation and tumor cell survival. Trunc=truncated; WT=wild type.

Figure 5.

Therapeutics selectively targeting truncated APC cells. In wild type (WT) APC cells, TASIN-1 induced cholesterol depletion leads to conformational change of SCAP protein which is then released from INSIG and assists SREBPs transport from endoplasmic reticulum (ER) to Golgi. SREBP is cleaved by proteases S1P and S2P in the Golgi and the cleaved form of SREBP then translocates into the nucleus and activates expression of genes involved in cholesterol synthesis and uptake. This compensates for reduced cellular level of cholesterol, thus cells survive. In contrast, truncated APC compromises the normal feedback mechanism in response to TASIN-1 treatment when cultured in low serum conditions, therefore cells undergo apoptotic cell death due to cholesterol depletion. HMGCR=3-hydroxy-3-methylglutaryl-CoA reductase; LDLR=low density lipoprotein receptor; TASIN-1=truncated APC selective inhibitor.