Activation of STAT3 and Bcl-2 and reduction of reactive oxygen species (ROS) promote radioresistance in breast cancer and overcome of radioresistance with niclosamide

Abstract

Radiotherapy significantly improves the therapeutic outcomes and survival of breast cancer patients. However, the acquired resistance to this therapeutic modality is a major clinical challenge. Here we show that ionizing irradiation (IR)-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) at the Tyr705 residue and the induction of reactive oxygen species (ROS) in wild-type and radioresistant MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines. Comparing with radiosensitive parental TNBC cells, significantly low levels of ROS and higher protein levels of phospho-STAT3 and Bcl-2 were observed in TNBC cells with acquired radioresistance. Moreover, knockdown of STAT3 by shRNA sensitized the TNBC cells to IR. Niclosamide, a potent inhibitor of STAT3, overcame the radioresistance in TNBC cells via inhibition of STAT3 and Bcl-2 and induction of ROS. In combination with radiation, niclosamide treatment resulted in significant increase of ROS generation and induction of apoptosis in parental and radioresistant TNBC cells in vitro and TNBC xenograft tumors in vivo. These findings demonstrate that activation of STAT3 and Bcl-2 and reduction of ROS contribute to the development of radioresistance in TNBC, and niclosamide acts as a potent radiosensitizer via inhibiting STAT3 and Bcl-2 and increasing ROS generation in TNBC cells and xenograft tumors. Our findings suggest that niclosamide in combination with irradiation may offer an effective alternative approach for restoring the sensitivity of radioresistant TNBC cells to IR for improved therapeutic efficacy and outcomes.

CPNE1 predicts poor prognosis and promotes tumorigenesis and radioresistance via the AKT singling pathway in triple‐negative breast cancer

“…Consistent with our results, other studies reported that MDA‐MB‐231 cells demonstrated a higher survival fraction than MDA‐MB‐468 cells after 2 or 4 Gy 28,29 . However, the differences in colony formation between MDA‐MB‐468 and MDA‐MB‐231 cells after 4 Gy were not significant 30 . It was recently reported that PI3K/AKT inhibitor inhibited the resistance to endocrine or DNA‐damaging radiotherapy in ER‐positive early patients with BC 31 .…”

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

“…HJC0152 also decreases the antioxidant capacity of A549 cells and increases ROS levels. When ROS is accumulated to a level higher than the antioxidant capacity of cells, oxidative stress occurs, leading to apoptosis . Our results also showed that HJC0152 induces apoptosis in A549 NSCLC cells.…”

“…Previously, we found that oxidative stress is an early upstream event of apoptosis in breast cancer cells . To assess whether HJC0152 induces apoptosis in lung cancer cells, we performed annexin V‐FITC/PI double staining and analysis using flow cytometry .…”

“…The lysates were then centrifuged (13 000 × g , 4°C) for 15 minutes to obtain total protein lysates. Protein expression was analysed using Western blotting as described previously . The expression level of GAPDH was used as the loading control.…”

“…We and others recently determined that niclosamide, a Food and Drug Administration-approved anthelmintic drug, 16 effectively suppresses the activation, nuclear translocation and transactivation of STAT3. 17,18 However, the further clinical development of niclosamide for cancer therapy is hindered by its poor water solubility and low oral bioavailability. We previously developed a series of O-alkylamino-tethered niclosamide derivatives, including HJC0152 ( Figure 1A).…”