Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response

Abstract

Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in many different cancers, including colorectal, breast, and prostate cancer, and its loss correlates with a decreased overall survival in cancer patients. While APC is commonly known for its role as a negative regulator of the WNT pathway, APC has numerous binding partners and functional roles. Through APC’s interactions with DNA repair proteins, DNA replication proteins, tubulin, and other components, recent evidence has shown that APC regulates the chemotherapy response in cancer cells. In this review article, we provide an overview of some of the cellular processes in which APC participates and how they impact chemoresistance through both epithelial- and TME-derived mechanisms.

SPTAN1, APC, and FGFR3 Mutation Status and APOBEC Mutation Signatures are Predictive of Mitomycin C Response in Non-muscle-invasive Bladder Cancer

“…Furthermore, APC mutations have been shown to induce chemoresistance through angiogenesis by interacting with the tumour microenvironment. This is supportive of a connection between APC mutation status and MMC resistance, considering that MMC works through reduction that is inhibited by oxygen and hence blood supply [17] , [18] . Lastly, in vivo studies showed that loss of APC was associated with chemoresistance through alterations of the immune cell infiltration [17] .…”

CircEAF2 counteracts Epstein-Barr virus-positive diffuse large B-cell lymphoma progression via miR-BART19-3p/APC/β-catenin axis

“…MiR-BART19-3p is implicated in the activation of Wnt signaling pathway by targeting tumor suppressor APC, enhancing proliferation and suppressing apoptosis of EBV-infected tumor cells [ 21 ]. APC can downregulate Wnt signaling pathway by reducing the accumulation of β-catenin in the nucleus, thereby inhibit tumor growth and chemoresistance in multiple cancer types [ 34 , 35 ]. Here in EBV-positive B-lymphoma cells, circEAF2 specifically targeted miR-BART19-3p, upregulated APC, and suppressed downstream β-catenin, indicative a viral miRNA-mediated mechanism underlying EBV + DLBCL progression.…”

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

“…Although the pathophysiological mechanisms that drive colorectal carcinogenesis are heterogeneous, the tumoral transformation of normal intestinal epithelial cells (IEC) depends on an event that triggers chromosomal instability (CIN) and the accumulation of somatic mutations and epigenetic alterations [ 20 , 61 , 62 ]. In this context, the deregulation of the Wnt/β-catenin signaling components is the most frequent event and leads to hyperproliferation in the intestinal crypt [ 63 , 64 ].…”