Radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector

Abstract

Surgery followed by radiotherapy is the standard treatment for chordomas, which are a rare but low-grade type of bone cancer arising from remnants of the embryonic notochord. However, disease recurrence following radiotherapy is common, most likely due to endogenous DNA repair mechanisms that promote cell survival upon radiation strikes. The ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3 related (ATM/ATR)-mediated pathway has a critical role in DNA repair mechanisms; however, it has rarely been investigated in chordomas. In the present study, the expression of signal molecules related to the ATM/ATR pathway in chordoma tissues and adjacent normal tissues were initially examined using immunohistochemistry and western blot analysis. Chordoma U-CH1 and U-CH2 cells were subsequently used to investigate cell responses to ionizing radiation and the potential protective actions mediated by the ATM/ATR pathway. Phosphorylated (p)-ATM, p-ATR, γ-H2A histone family, member X (H2AX) and RAD51 were significantly upregulated in chordoma tissues relative to adjacent normal tissues (P<0.05). No significant reductions were observed in the viability of U-CH1 and U-CH2 cells following exposure to low-dose (1 and 2 Gy) radiation. Radiation (1 and 2 Gy) triggered a significant upregulation in p-ATM, γ-H2AX and RAD51 expression in U-CH1 cells (P<0.05), as well as a significant upregulation in p-ATM, p-ATR and RAD51 levels in U-CH2 cells (P<0.05). RAD51 knockdown increased the responses of both U-CH1 and U-CH2 cells to 1 Gy radiation, as evidenced by the significantly decreased cell viability and increased apoptosis rate (P<0.05). Collectively, the results of the present study indicated that radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector. Thus, RAD51 presents a promising therapeutic target for improving the outcome of radiotherapy treatment in chordomas.

Aldehyde Dehydrogenase, a Therapeutic Target in Chordoma: Analysis in 3D Cellular Models

“…We thus speculate that the quiescent and low dividing subclones must be at the origin of radioresistance in this cell line. Confirming this hypothesis, the second study evaluated the response of the U-CH1 cell line to ionizing radiation and found the same rate of survival at 2Gy of X-rays as ours [41]. The variable degrees of radioresistance found can also be explained by the differences in proliferation, composition of extracellular matrix, and hypoxia.…”

“…Such an effect has never been obtained in vitro in chordoma, making ALDH a promising target for future preclinical experiments. Interestingly, the inhibition of RAD51 has been shown to sensitize chordoma cells to radiations in vitro [ 41 ]. Moreover, this inhibition also sensitizes cells to aldehyde treatment, substrates of ALDH activity [ 51 ].…”

miRNA‐106a and prostate cancer radioresistance: a novel role for LITAF in ATM regulation

“…ATM overexpression has been correlated with poor response to radiotherapy and worse overall survival in rectal cancer and advanced nasopharyngeal carcinoma patients (Ho et al, 2016;Ko et al, 2016). High ATM protein levels have been associated with radioresistance in primary glioma, chordoma, and breast cancer cells (Tribius et al, 2001;Yin and Glass, 2011;Zhang et al, 2017). Fraser et al found that somatic ATM mutations are associated with poor prognosis in localized prostate cancer (Fraser et al, 2017).…”

Chordoma: Etiology, Pathogenesis, Diagnosis, Treatment

“…Допускается, что радиорезистентность хордомы связана с эндогенными механизмами репарации ДНК, которые способствуют выживанию клеток при лучевой нагрузке [29]. Эти механизмы обеспечиваются, в частности, серин/треониновой киназой и белком RAD51.…”

“…Эти механизмы обеспечиваются, в частности, серин/треониновой киназой и белком RAD51. В ткани хордомы, в сравнении с окружающей здоровой тканью, уровень RAD51 значительно выше [29]. Путем гомологичной рекомбинации RAD51 восстанавливает разрыв, используя в качестве образца похожую или идентичную молекулу ДНК.…”