Abstract
Diphtheria toxin-like ADP-ribosyltransferases 1 and 5 (ARTD-1, ARTD-5) are poly ADP-ribose enzymes (PARP) involved in non-homologous end-joining (NHEJ), which is the major pathway of double-strand break (DSB) repair. In addition, ARTD-5, or Tankyrase (TNKS), is a positive regulator of the WNT signaling implicated in the development and biological behavior of many neoplasms, such as Medulloblastoma (MB), in which radiotherapy is an essential part of the treatment. The use of radiosensitizing agents may improve the therapeutic index in MB patients by increasing the efficacy of radiotherapy, while reducing toxicity to the neuroaxis. ARTD-5 seems to be a good molecular target for improving the current treatment of MB. In this study, we used the small molecule XAV939, a potent ARTD-5 inhibitor with a slight affinity for ARTD-1, in different human MB cell lines. XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences. The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality. In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients.
Highlights
ARTDs, a superfamily of 17 proteins, play a crucial role in different cellular functions such as DNA damage detection and repair, chromatin modification, mitotic apparatus formation, and cell death by transferring ADP-ribose unit or units onto specific molecular targets
Total β-catenin protein levels decreased by about 30% in both cell lines compared to controls; whereas, in nuclear fraction, we found an 80% reduction of β-catenin levels (Fig 1A)
Since TNKS PARP activity is critical for DNA-PK catalytic subunit (DNA-PKcs) stability [11], we tested whether XAV939 treatment affected DNA-PKcs protein levels in our cell lines
Summary
ARTDs, a superfamily of 17 proteins, play a crucial role in different cellular functions such as DNA damage detection and repair, chromatin modification, mitotic apparatus formation, and cell death by transferring ADP-ribose unit or units onto specific molecular targets (a posttranslational modification process referred to as “PARsylation”). Given this essential role in DNA mechanism repair, several studies have been carried out to explore the therapeutic potential of ARTDs specific inhibitors. The ARTD family member, ARTD-5, otherwise known as tankyrase (TNKS) has been shown to be involved in a multitude of critical cellular processes; it consists of two isoforms (TNKS1 and TNKS2), which share 85% amino acid sequence identity and have overlapping functions [7,8,9,10]
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