Torin2 enhances the radiosensitivity of MCF‑7 breast cancer cells by downregulating the mTOR signaling pathway and ATM phosphorylation

Abstract

Radiotherapy has an important role in the comprehensive treatment of breast cancer. However, the clinical outcome of adjuvant radiotherapy may be limited due to intrinsic radioresistance, it is necessary to explore efficient radiosensitization methods that improve the clinical outcome of patients undergoing radiotherapy. The present study aimed to investigate whether the novel mechanistic target of rapamycin (mTOR) inhibitor Torin2 enhances the radiosensitivity of MCF‑7 breast cancer cells. A Cell Counting Kit‑8 (CCK‑8) assay was performed to measure the effect of Torin2 on cell proliferation, while clonogenic assays were employed to determine the effect of Torin2 in combination with radiation on the proliferation of MCF‑7 cells. The effect of Torin2 and/or radiation on the cell cycle was analyzed using flow cytometry. Furthermore, the protein expression of components of the phosphatidylinositol 3‑kinase/Akt/mTOR pathway, and the expression of proteins involved in DNA damage repair, was measured by western blot analysis. The results demonstrated that Torin2 exhibited a higher potency in MCF‑7 cells, while MDA‑MB‑231 cells were less sensitive to Torin2. Compared with irradiation alone, pretreatment with 20 nM Torin2 followed by irradiation resulted in an increased level of γ‑H2A histone family member X. Radiation induced the activation of the Akt/mTOR signaling pathway and upregulated the expression of phosphorylated (p)‑Akt473 and p‑eukaryotic translation initiation factor 4E binding protein 1 (4EBP1)37/46. Notably, pretreatment with Torin2 attenuated the radiation‑induced activation of the Akt/mTOR signaling pathway. In addition, Torin2 partially blocked the repair of double‑strand breaks induced by radiation by reducing the activation of ataxia telangiectasia‑mutated, and sensitized MCF‑7 cells to radiation. In conclusion, administration of Torin2 prior to irradiation enhanced the radiotherapeutic effect on breast cancer cells in vitro, and these results may provide a foundation for the rational use of combined therapy with irradiation and Torin2 for breast cancer in clinical practice.

A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

“…The activation of these pathways protects cancer cells from the cytotoxic effects of radiation, ultimately leading to the development of radioresistance [ 9 ]. The activation of PI3K/AKT is highly involved in the development of radioresistance in several solid tumors including breast, lung, and prostate cancers [ 10 – 12 ]. Therefore, targeting these survival pathways in combination with radiotherapy may enhance therapeutic efficacy in breast cancer by attenuating cellular defense in response to treatment.…”

Targeting the mTOR pathway using novel ATP‑competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma

“…Furthermore, investigators have also found that Torin2 was effectively cytotoxic against tumor cells and not cytotoxic to the non-malignant cells. Pre-treatment with Torin2 enhanced the efficacy of radiotherapy in breast cancer cells ( 49 ). Consistent with these findings, the results of the present study showed a significant effect of both Torin1 and Torin2 in suppressing cell growth and proliferation, with Torin2 demonstrating a higher degree of efficacy.…”

Torin2 inhibits the EGFR-TKI resistant Non-Small Lung Cancer cell proliferation through negative feedback regulation of Akt/mTOR signaling

“…It is reported that torin2 also inhibited cellular activity against phosphatidylinositol 3-kinase-related kinase (PIKK) family kinases including ataxia telangiectasia-mutated kinase (ATM), ataxia telangiectasia-mutated, Rad3-related kinase (ATR) and DNA-PK, the inhibition of which sensitized cells to irradiation [45]. Luo et al showed that torin2 could enhance the radiosensitivity of breast cancer cells by downregulation the mTOR signaling and ATM phosphorylation [46]. Moreover, torin2 inhibited lionizing radiation-induced DNA damage repair [47].…”