Laboratory of Genome Stability Maintenance, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo, Japan.
Department of Biological Science and Technology, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan.
PLoS One. 2023 Jan 27;18(1):e0281168. doi: 10.1371/journal.pone.0281168. eCollection 2023.
Malignancy is often associated with therapeutic resistance and metastasis, usually arising after therapeutic treatment. These include radio- and chemo-therapies, which cause cancer cell death by inducing DNA double strand breaks (DSBs). However, it is still unclear how resistance to these DSBs is induced and whether it can be suppressed. Here, we show that DSBs induced by camptothecin (CPT) and radiation jeopardize genome stability in surviving cancer cells, ultimately leading to the development of resistance. Further, we show that cytosolic DNA, accumulating as a consequence of genomic destabilization, leads to increased cGAS/STING-pathway activation and, ultimately, increased cell migration, a precursor of metastasis. Interestingly, these genomic destabilization-associated phenotypes were suppressed by the PARP inhibitor Olaparib. Recognition of DSBs by Rad51 and genomic destabilization were largely reduced by Olaparib, while the DNA damage response and cancer cell death were effectively increased. Thus, Olaparib decreases the risk of therapeutic resistance and cell migration of cells that survive radio- and CPT-treatments.
恶性肿瘤通常与治疗抵抗和转移有关，通常在治疗后出现。这些治疗包括放射治疗和化学治疗，它们通过诱导 DNA 双链断裂（DSBs）来导致癌细胞死亡。然而，目前尚不清楚如何诱导对这些 DSB 的抵抗，以及是否可以抑制这种抵抗。在这里，我们表明喜树碱（CPT）和辐射诱导的 DSBs 会危及存活癌细胞的基因组稳定性，最终导致耐药性的产生。此外，我们还表明，由于基因组不稳定而积累的细胞质 DNA 会导致 cGAS/STING 通路的激活增加，最终导致细胞迁移增加，这是转移的前兆。有趣的是，这些与基因组不稳定相关的表型可以被 PARP 抑制剂奥拉帕尼抑制。奥拉帕尼抑制 Rad51 对 DSB 的识别和基因组不稳定，同时有效地增加了 DNA 损伤反应和癌细胞死亡。因此，奥拉帕尼降低了放射治疗和 CPT 治疗后存活的细胞发生治疗抵抗和细胞迁移的风险。
