Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

Abstract

The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.

Morin‐dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW‐PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in an Apc‐driven model of colon cancer

“…Taken together these data suggest that Apc mutated cells express high LMW‐PTP levels and that LMW‐PTP levels increase in the process of colon carcinogenesis. Apc mutations have been linked to constitutive activation of the Wnt‐signaling pathway causing up/down regulation of several genes connected with cell proliferation and differentiation . So far, LMW‐PTP has not been described as a possible target of the Wnt‐signaling, but it is possible that, at least indirectly, this protein may be linked to the activation of the Wnt‐pathway, a hypothesis that should be verified in the future.…”

“…In addition, we find that in the tumors from animals treated with morin, apoptosis is higher than in those from control animals, suggesting that this phenomenon might selectively favor the elimination of defective cells during carcinogenesis. An increase in apoptosis in tumors, has been described as a mechanism through which chemopreventive agents act in the colon . Interestingly, basal levels of apoptosis in the normal mucosa are not affected by morin.…”

Identification of driver genes and somatic mutations in cell‐free DNA of patients with pulmonary lymphangioleiomyomatosis

“…Mismatch repair genes ( BLM and MLH3 ) can increase the risk of developing BC and OC . Inactivation of tumor suppressor gene APC contributes to colorectal cancer via interacting with β‐catenin to inhibit canonical Wnt signaling . These might therefore provide a powerful gist for characterizing LAM disease shared mutual genetic risk factors with cancers, particularly BC and OC.…”

Familial Pancreatic Cancer

“…EPCAM is involved in cell-matrix or cell-cell adhesion [51]. Familial adenomatous polyposis (FAP) is also autosomal dominant and contains mutations in APC, which is connected to the WNT signaling; the risk for developing PDAC with FAP is lower than 5% [11,52,53]. Ataxia telangiectasia (ATM) is autosomal recessive and the life time risk is also less than 5% for developing PDAC [25,54,55,56].…”