Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/β-catenin signaling pathway in taxol-resistant human lung adenocarcinoma

Abstract

Background: Chemotherapy is one of the primary treatments for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), however, chemoresistance develops over time and is a bottleneck to effective chemotherapy worldwide. Therefore, the development of new potent therapeutic agents to overcome chemoresistance is of utmost importance. Triptolide is a natural component extracted from Tripterygium Wilfordii, a Chinese plant; our study aimed to evaluate its anti-tumor effects in taxol-resistant human lung adenocarcinoma and investigate its molecular mechanisms of chemoresistance.Methods: Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot.Expression of β-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3α/β was evaluated by western blot and IHC.Results: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxolresistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelialmesenchymal transition (EMT) through repression of the p70S6K/GSK3/β-catenin signaling pathway. Conclusions:Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/β-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.

Circular RNA circβ‐catenin aggravates the malignant phenotype of non‐small‐cell lung cancer via encoding a peptide

“…Therefore, we speculated that circβ-catenin-370aa, a novel peptide, circβ-catenin re- it is known that β-catenin can increase the malignant phenotype of NSCLC. 41,42,56 In summary, these results indicated that circβ-catenin encoded β-catenin-370aa to combine with GSK3β, leading to escape the degradation of β-catenin induced by GSK3β.…”

“…Since β‐catenin was a cancer‐promoting transcription factor of NSCLC and other cancers, 37–42 we speculated that circβ‐catenin in NSCLC cell might directly or indirectly affect β‐catenin expression. To clarify whether there was an interaction between circβ‐catenin and β‐catenin, we designed and synthesized small interference RNA to knockdown β‐catenin expression.…”

“…co‐IP results confirmed that circβ‐catenin knockdown or overexpression was able to enhance or reduce the combination between GSK3β and β‐catenin. In addition, it is known that β‐catenin can increase the malignant phenotype of NSCLC 41,42,56 …”

“…Since β-catenin was a cancer-promoting transcription factor of NSCLC and other cancers, [37][38][39][40][41][42] we speculated that circβ-catenin in NSCLC cell might directly or indirectly affect β-catenin expression.…”

Triptolide impairs LUAD cells through the JAK-STAT signaling pathway by activating autophagy

“…Triptolide (TPL), an extract from the Chinese herb Tripterygium wilfordii, has been reported to have antitumor effects on many malignant tumors, such as ovarian cancer [2], oral cancer [3], pancreatic cancer [4], breast cancer [5,6], colon carcinoma [7] and lung cancer [8][9][10]. Our previous study demonstrated that TPL could inhibit tumor growth and induce apoptosis in Taxol-resistant LUAD cells [11]. However, the molecular mechanism by which TPL affects the of autophagy in LUAD remains poorly understood.…”