Crosstalk between Wnt/β-catenin signaling pathway and DNA damage response in cancer: a new direction for overcoming therapy resistance

Abstract

Wnt signaling plays an important role in regulating the biological behavior of cancers, and many drugs targeting this signaling have been developed. Recently, a series of research have revealed that Wnt signaling could regulate DNA damage response (DDR) which is crucial for maintaining the genomic integrity in cells and closely related to cancer genome instability. Many drugs have been developed to target DNA damage response in cancers. Notably, different components of the Wnt and DDR pathways are involved in crosstalk, forming a complex regulatory network and providing new opportunities for cancer therapy. Here, we provide a brief overview of Wnt signaling and DDR in the field of cancer research and review the interactions between these two pathways. Finally, we also discuss the possibility of therapeutic agents targeting Wnt and DDR as potential cancer treatment strategies.

Keywords: DNA damage response; Wnt; cancer; drug resistance; therapy.

FIGURE 1

Introduction of the Wnt signaling pathway. Wnt OFF: In the absence of Wnt ligand, β-catenin binds to the destruction complex which comprises AXIN, CK1α, GSK-3β, and APC. Subsequently, a series of phosphorylation events occur to create a docking site on β-catenin for β-TrCP, and then β-catenin is ubiquitinated by β-TrCP and subjected to ubiquitin-proteasomal degradation. Wnt ON: In the presence of Wnt ligands, Frizzled receptors and the co-receptors LRP5/6 multimerize at the cell surface. This leads to recruitment of the cytoplasmic protein Dvl to the cell membrane by interacting with cytoplasmic domains of Frizzled receptors. The Frizzled-bound Dvl recruits the destruction complex through Dvl and axin, GSK-3β in the destruction complex initiates phosphorylation of the LRP5/6 and subsequent phosphorylation by CK1s, and more destruction complexes are recruited to the cell membrane that further phosphorylate LRP5/6 as a positive feedback loop. Wnt Ca²⁺: Wnt/Frizzled ligand receptor interaction with the participating co-receptor ROR1/2 leads to the activation of PLC and then hydrolyzes PIP2 into products IP3 and DAG. IP3 causes the release of Ca²⁺ from the endoplasmic reticulum, and two kinases CaMKII and Cn are activated, which in turn activate NFAT and NF-κB. DAG is activated by released calcium from the endoplasmic reticulum. Subsequently, PKC is activated which then activates NF-κB and CREB. These factors translocate to the nucleus where downstream gene expression is regulated. Wnt PCP: In the planar cell polarity pathway, after binding to Frizzled receptors and recruiting Dvl, which forms a complex with DAAM1, Wnt then activates the small GTPase Rho, which in turn activates ROCK. Alternatively, Dvl could also form a complex with RAC to activate JNK and then increase JNK-dependent c-JUN transcription activity.

FIGURE 2

Introduction of DDR. PARP-1: PARP-1 detects and binds to damaged DNA and subsequently synthesizes poly (ADP) ribose (pADPr) on acceptor proteins. The high-density negative charge of pADPr gradually accumulates, leading to PARP-1 release from DNA simultaneously with the recruitment of DNA repair protein complex. Lastly, after the DNA break is repaired, the repair complex is dissociated from DNA and poly (ADP-ribose) glycohydrolase (PARG), and ADP-ribose hydrolase 3 (ARH3) hydrolyzes pADPr into ADP-ribose molecules and free pADPr. DNA-PKcs: DSBs are rapidly bound by the Ku heterodimer (Ku70 and Ku80) and loads onto DSB ends. Within seconds, Ku loads and activates DNA-PKcs to initiate NHEJ. Additional NHEJ core factors are subsequently recruited for the ends to be closely aligned and ligated. ATM: The MRN complex recruits ATM to DNA lesions and stimulates ATM kinase activity in response to DSBs. ATM phosphorylates histone H2AX and MDC1 in response to DSBs and lays the foundation for the chromatin-based signaling cascade involving phosphorylation and ubiquitination, which are mediated by RNF8 and RNF168 that results in ubiquitination of H2A to promote recruitment of 53BP1, which recruits its effectors to repair lesion. In addition, ATM phosphorylation activates Chk1/2, which in turn influences downstream factor cell to arrest the cell cycle. ATR: After suffering various forms of damaged DNA or helicase-polymerase uncoupling at stalled replication forks, RPA coats the ssDNA protecting it from degradation. ATR is recruited to RPA-ssDNA by its partner protein ATRIP and activated by TopBP1 or ETAA1; TopBP1 plays a role in ATR activation, which requires interaction with the RAD9–HUS1–RAD1 (9-1-1) clamp complex. ETAA1 is recruited to RPA-ssDNA via direct binding to RPA. In the downstream, ATR signaling activates the CHK1 kinase. CHK1 activation causes CDC25A degradation and slowing of cell cycle progression to arrest the cell cycle.

FIGURE 3

Schematic diagram showing that Wnt signaling is highly intertwined with DDR. LRP, lipoprotein receptor-related protein; APC, adenomatous polyposis coli; GSK-3β, glycogen synthase kinase-3β; CK1α, casein kinase 1α; TCF, T lymphocytokine/lymphoenhancer factor; LEF, human lymphoid enhancer factor; PARP, poly (ADP) ribose polymerase; ATM, ataxia telangiectasia mutated proteins; ATR, ataxia telangiectasia and Rad3-related protein; CHK, checkpoint kinase; ARF, ADP-ribosylation factor; MDM2, murine double minute 2.