Celastrol elicits antitumor effects by inhibiting the STAT3 pathway through ROS accumulation in non-small cell lung cancer

Abstract

Background Non-small cell lung cancer (NSCLC) is the most common lung cancer with high mortality across the world, but it is challenging to develop an effective therapy for NSCLC. Celastrol is a natural bioactive compound, which has been found to possess potential antitumor activity. However, the underlying molecular mechanisms of celastrol activity in NSCLC remain elusive. Methods Cellular function assays were performed to study the suppressive role of celastrol in human NSCLC cells (H460, PC-9, and H520) and human bronchial epithelial cells BEAS-2B. Cell apoptosis levels were analyzed by flow cytometry, Hoechst 33342, caspase-3 activity analysis, and western blot analysis. Intracellular reactive oxygen species (ROS) were analyzed by flow cytometry and fluorescence microscope. Expression levels of endoplasmic reticulum (ER) stress-related proteins and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) were identified via western blot analysis. A heterograft model in nude mice was employed to evaluate the effect of celastrol in vivo. Results Celastrol suppressed the growth, proliferation, and metastasis of NSCLC cells. Celastrol significantly increased the level of intracellular ROS; thus, triggering the activation of the ER stress pathway and inhibition of the P-STAT3 pathway, and eventually leading to cell apoptosis, and the effects were reversed by the pre-treatment with N-Acetyl-l-cysteine (NAC). Celastrol also suppressed tumor growth in vivo. Conclusion The outcomes revealed that celastrol plays a potent suppressive role in NSCLC in vitro and in vivo. Celastrol induces apoptosis via causing mitochondrial ROS accumulation to suppress the STAT3 pathway. Celastrol may have potential application prospects in the therapy of NSCLC.

MIOX inhibits autophagy to regulate the ROS -driven inhibition of STAT3/c-Myc-mediated epithelial-mesenchymal transition in clear cell renal cell carcinoma

“…Previous studies indicated that autophagy inhibition could lead to ROS accumulation [ 50 ]. Moreover, ROS inhibited p-STAT3 and interfered with downstream signal transduction of STAT3 in some cancer types [ 51 , 52 ]. We further investigated whether MIOX upregulated ROS levels by inhibiting autophagy, thereby mediating the inhibition of the STAT3/c-Myc signaling axis.…”

Identification of ATAD3A as a key regulator in non‐small cell lung cancer by promoting STAT3‐induced cell proliferation and tumor angiogenesis

“…ATAD3A is a mitochondrial protein and part of the STAT3 localized at the organelle. Both contribute to the tumorigenic process by regulating mitochondrial homeostasis and dynamics in different tumors 8,29 . Thus, we hypothesize changes in ATAD3A expression in lung cancer cells may affect mitochondrial function and promotes the phosphorylation of STAT3 activation and nuclear translocation to regulate the expression of proliferation, angiogenesis‐related genes, leading to tumor growth and angiogenesis.…”

Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer

“…STAT3 was first identified as an oncogene required for epithelial cell transformation ( 6 ). The STAT3 pathway is frequently overactive in NSCLC, and STAT3 expression correlates with poor survival, making it a promising target for the design of novel cancer drugs ( 7 ). In addition, reactive oxygen species (ROS) act as critical intracellular messengers in cell proliferation, differentiation, and survival ( 8 ).…”