Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via hsa-miR-542-5p

Abstract

Blocking ataxia telangiectasia mutated (ATM), a crucial player in DNA repair responses, has been proposed as a promising strategy in anti-cancer therapy. Most previous studies have focused on DNA damage response-related pathways after administration of ATM inhibitors. However, ATM inhibition could potentially influence a wide range of changes in gene expression, which remain poorly defined. Here, we report that administration of the ATM inhibitor KU60019 led to impaired migration and enhanced apoptosis in the ovarian cancer cell line SKOV3, accompanied by abnormally elevated O-GlcNAc transferase and O-GlcNAcase expression levels. In addition, KU60019 treatment significantly suppressed expression of hsa-miR-542-5p in SKOV3 cells. Up-regulation of hsa-miR-542-5p expression inhibited increases in OGT and OGA level, and reversed the effects of ATM inhibition on apoptosis and migration in SKOV3 cells. Finally, we found aberrant expression of OGT and OGA to be associated with ovarian cancer patient survival. Taken together, our results suggest that ATM inhibition may promote SKOV3 cell apoptosis via suppressing hsa-miR-542-5p and elevating OGT and OGA expression, providing new insights into the application of ATM inhibitors in cancer immunotherapy.

KU60019 induced ATM blockage regulates GPR91/has-miR-576-3p to inhibit ovarian cancer progression

“…Ataxia telangiectasia mutated (ATM) could be activated in response to DNA damage, which lead to phosphorylation of downstream proteins to regulate apoptosis and cell cycle in cancer (12). It was reported that loss of ATM prolonged the diestrus phase in mice, ATM inhibition suppressed phosphoramide mustard induced destroys primordial follicles (13).…”

RYBP Sensitizes Cancer Cells to PARP Inhibitors by Regulating ATM Activity

“…We attribute the differences in the results between U2OS and SKOV3 cells to the higher resistance of SKOV3 to PARP inhibitors and to the higher ATM activity previously reported in ovarian cancer cells [ 27 , 36 ]. A recent study showed that inhibiting ATM activity by KU-60019 in SKOV3 resulted in cell apoptosis [ 40 ]. However, it was shown that KU-60019 is 10-fold more effective than KU-55933 (the ATM inhibitor used in our study) at blocking radiation-induced phosphorylation of ATM and its targets [ 41 ].…”

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

“…Multiple preclinical studies have analyzed the efficacy of ATM inhibitors in monotherapy or in combination with other chemotherapeutic drugs in several tumors, including OCs (Table 4). In general, these inhibitors decreased OC cell proliferation and synergized with other compounds, such as fenofibrate, an inhibitor of PPARA, 673A, or DNA-damaging agents, including ionizing radiation, trabectedin, and lurbinectedin [123][124][125][126]275].…”

“…Inhibition of cell migration and induction of apoptosis [123]. Synergistic cytotoxic effect in combination with fenofibrate (PPARA inhibitor) [123].…”

“…Inhibition of cell migration and induction of apoptosis [123]. Synergistic cytotoxic effect in combination with fenofibrate (PPARA inhibitor) [123]. Sensitization to ionizing radiation, trabectedin, and lurbinectedin [124,125] AZD0156 ATM Synergistic cytotoxic effect in combination with fenofibrate (PPARA inhibitor) [123] KU-55933 ATM Sensitization to ionizing radiation, trabectedin and lurbinectedin [124,125] AZD1390 ATM Synergistic cytotoxic effect in combination with an aldehyde dehydrogenase 1 inhibitor (67A) [126].…”