Non-toxic anti-cancer treatment may be possible by targeting an appropriate cancer cell

The anti-tumor agent, Cisplatin and/or ionizing radiation are commonly used in cancer therapy. During DNA replication, cisplatin induces double-strand breaks by forming DNA interstrand crosslinks. Ionizing radiation immediately causes single- and double-strand breaks in DNA. Cancer treatments with cisplatin/ionizing radiation induce DNA damage and rapidly kill growing tumors. However, when an error-free DNA repair pathway, including homologous recombination is decreased, the breaks in DNA caused by ionizing radiation or cisplatin are sometimes repaired via error-prone DNA repair pathways, which result in higher genomic instability.

The RecQ helicase family is essential for the maintenance of genomic stability. They were conserved from RECQ in bacteria to RECQL1, BLM, WRN, RECQL4 and RECQL5 in humans. Hereditary susceptibility to cancer syndromes like Rothmund–Thomson syndrome (RTS) type II, in addition to Baller– Gerold syndrome (BGS) and RAPADILINO syndrome are associated with germline mutations of RECQL4. There is yet to be any effective therapy for cancers developed by patients who present with RECQL4-associated diseases. Studies using RECQL4 siRNA have revealed that RECQL4 is involved in double-strand DNA breaks repair via 2 major pathways, homologous recombination (a representative error-free DNA repair pathway) and non-homologous end joining (error-prone DNA repair pathway), although the expression of an essential RECQL4 Sld2 domain can be significantly affected by RECQL4 siRNA treatment. It is yet to be determined what role RECQL4 plays in other error-prone pathways.

To explore the role of RECQL4 in other error-prone DNA repair pathways, University of Occupational and Environmental Health researchers: Masaoki Kohzaki et al., showed that RECQL4ΔC cancer cells are hypersensitive to cisplatin/ionizing radiation and they induce an increase in RPA2/RAD52 foci following cancer treatments This work is published in the International Journal of Cancer.

The research team found that RECQL4ΔC cancer cells not the nonmalignant cells displayed a hypersensitivity to cisplatin/ionizing radiation. This may be due to a deficiency in the helicase and C-terminal domain of RECQL4. They also observed that following cancer treatments, RECQL4ΔC cancer cells stimulated RAD52/RPA2. Using GFP-reporter assay, they noticed that RECQL4ΔC cancer cells induced the activity of error-prone single-strand annealing (SSA) but suppressed the DNA repair actions of alternative end-joining (Alt-EJ). Given that SSA and Alt-EJ share a common DNA repair substrate, this DNA repair property of RECQL4-deficient cancer cells are unique.

The author carried out RAD52-suppression experiments using different RAD52 inhibitors and peptides essential for the RAD52 ssDNA binding for SSA activity, and the results suggest that specific inhibition of RAD52 kills RECQL4ΔC cancer cells that have been upregulated by RAD52. In vivo experiments in mice also showed that inhibition of RAD52 effectively restrained RECQL4ΔC cancer cells upregulated by RAD52. Importantly, regression of RECQL4ΔC cancer cells was observed at a very low dose of Epigallocatechin (EGC), equivalent to 1.5 cups of green tea, suggesting that nearly non-toxic anti-cancer treatment would be possible when we target cancer cells with specific DNA repair property.

They found that cisplatin treatment followed by RAD52 inhibition at a timing SSA activity increased (~24h) caused growth suppression of RECQL4ΔC cancer cells. Therefore, RAD52 inhibitors can be used not only as a single agent but also in combination with cisplatin at the appropriate timing of administration. In addition, cisplastin treatment induced large gene deletions, and these large deletions were not observed with RAD52 inhibitor after cisplatin treatment in RECQL4ΔC HCT116 cells.

In a nut shell, the scientists responsible for the study were able to identify potential targets for cancer therapy that might be beneficial for cancer patients with upregulated RAD52 or RECQL4 gene mutations. The development of treatment regimens that target the single-strand annealing pathway mediated by RAD52 after cancer treatment may prove useful in patients with RECQL4 gene mutations.