Abstract：
BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy in the world with an alarming rate of mortality. Despite the advancement in treatment strategies and drug developments, the overall survival rate remains poor. Therefore, it is imperative to develop alternative or complimentary anti cancer drugs with minimum off target effects. Urolithin A, a microbial metabolite of ellagic acid and ellagitannins produced endogenously by human gut micro biome is considered to have anti-cancerous activity. However anti tumorigenic effect of urolithin A in OSCC is yet to be elucidated. In this study, we examined whether urolithin A inhibits cell growth and induces both apoptosis and autophagy dependent cell death in OSCC cell lines.
OBJECTIVE: The present study aims to evaluate the potential of urolithin A to inhibit OSCC and its regulatory effect on OSCC proliferation and invasion in vitro and in vivo mouse models.
METHODS: We evaluated whether urolithin A could induce cell death in OSCC in vitro and in vivo mouse models.
RESULTS: Flow cytometric and immunoblot analysis on Urolithin A treated OSCC cell lines revealed that urolithin A markedly induced cell death of OSCC via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. This further revealed a possible cross talk between apoptotic and autophagic signaling pathways. In vivo study demonstrated that urolithin A treatment reduced tumor size and showed a decrease in mTOR, ERK1/2 and Akt levels along with a decrease in proliferation marker, Ki67. Taken together, in vitro as well as our in vivo data indicates that urolithin A is a potential anticancer agent and the inhibition of AKT/mTOR/ERK signalling is crucial in Urolithin A induced growth suppression in oral cancer.
CONCLUSIONS: Urolithin A exerts its anti tumorigenic activity through the induction of apoptotic and autophagy pathways in OSCC. Our findings suggest that urolithin A markedly induced cell death of oral squamous cell carcinoma via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. Urolithin A remarkably suppressed tumor growth in both in vitro and in vivo mouse models signifying its potential as an anticancer agent in the prevention and treatment of OSCC. Henceforth, our findings provide a new insight into the therapeutic potential of urolithin A in the prevention and treatment of OSCC.
OBJECTIVE: The present study aims to evaluate the potential of urolithin A to inhibit OSCC and its regulatory effect on OSCC proliferation and invasion in vitro and in vivo mouse models.
METHODS: We evaluated whether urolithin A could induce cell death in OSCC in vitro and in vivo mouse models.
RESULTS: Flow cytometric and immunoblot analysis on Urolithin A treated OSCC cell lines revealed that urolithin A markedly induced cell death of OSCC via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. This further revealed a possible cross talk between apoptotic and autophagic signaling pathways. In vivo study demonstrated that urolithin A treatment reduced tumor size and showed a decrease in mTOR, ERK1/2 and Akt levels along with a decrease in proliferation marker, Ki67. Taken together, in vitro as well as our in vivo data indicates that urolithin A is a potential anticancer agent and the inhibition of AKT/mTOR/ERK signalling is crucial in Urolithin A induced growth suppression in oral cancer.
CONCLUSIONS: Urolithin A exerts its anti tumorigenic activity through the induction of apoptotic and autophagy pathways in OSCC. Our findings suggest that urolithin A markedly induced cell death of oral squamous cell carcinoma via the induction of endoplasmic reticulum stress and subsequent inhibition of AKT and mTOR signaling as evidenced by decreased levels of phosphorylated mTOR and 4EBP1. Urolithin A remarkably suppressed tumor growth in both in vitro and in vivo mouse models signifying its potential as an anticancer agent in the prevention and treatment of OSCC. Henceforth, our findings provide a new insight into the therapeutic potential of urolithin A in the prevention and treatment of OSCC.
摘要：
背景：口腔鳞状细胞癌（OSCC）是世界上最常见的恶性肿瘤，死亡率惊人。尽管在治疗策略和药物开发方面取得了进展，总体生存率仍然很低。因此,必须开发具有最小脱靶效应的替代或免费抗癌药物。尿磷脂A,由人类肠道微生物组内源性产生的鞣花酸和鞣花单宁的微生物代谢产物被认为具有抗癌活性。然而，尿石素A在OSCC中的抗肿瘤作用尚未阐明。在这项研究中,我们研究了尿石素A是否在OSCC细胞系中抑制细胞生长并诱导细胞凋亡和自噬依赖性细胞死亡。
目的：本研究旨在评估尿石素A在体外和体内小鼠模型中抑制OSCC的潜力及其对OSCC增殖和侵袭的调节作用。
方法：我们在体外和体内OSCC小鼠模型中评估尿石素A是否可以诱导细胞死亡。
结果:对尿石素A处理的OSCC细胞系的流式细胞术和免疫印迹分析显示尿石素A通过诱导内质网应激和随后的AKT和mTOR信号传导的抑制显著诱导OSCC的细胞死亡,如磷酸化mTOR和4EBP1水平降低所证明的。这进一步揭示了凋亡和自噬信号通路之间可能的串扰。体内研究表明，尿石素A治疗可减小肿瘤大小，并显示mTOR减少，ERK1/2和Akt水平随着增殖标志物的降低，Ki67.一起来看,体外以及我们的体内数据表明,尿石素A是一种潜在的抗癌剂,而AKT/mTOR/ERK信号的抑制对于尿石素A诱导的口腔癌生长抑制至关重要.
结论：尿石素A通过诱导OSCC细胞凋亡和自噬途径发挥其抗肿瘤活性。我们的发现表明，尿石素A通过诱导内质网应激和随后的AKT和mTOR信号传导的抑制显着诱导口腔鳞状细胞癌的细胞死亡，磷酸化mTOR和4EBP1水平降低证明了这一点。尿石素A在体外和体内小鼠模型中均显着抑制肿瘤生长，表明其作为预防和治疗OSCC的抗癌剂的潜力。从今以后,我们的研究结果为尿石素A在预防和治疗OSCC方面的治疗潜力提供了新的见解.
目的：本研究旨在评估尿石素A在体外和体内小鼠模型中抑制OSCC的潜力及其对OSCC增殖和侵袭的调节作用。
方法：我们在体外和体内OSCC小鼠模型中评估尿石素A是否可以诱导细胞死亡。
结果:对尿石素A处理的OSCC细胞系的流式细胞术和免疫印迹分析显示尿石素A通过诱导内质网应激和随后的AKT和mTOR信号传导的抑制显著诱导OSCC的细胞死亡,如磷酸化mTOR和4EBP1水平降低所证明的。这进一步揭示了凋亡和自噬信号通路之间可能的串扰。体内研究表明，尿石素A治疗可减小肿瘤大小，并显示mTOR减少，ERK1/2和Akt水平随着增殖标志物的降低，Ki67.一起来看,体外以及我们的体内数据表明,尿石素A是一种潜在的抗癌剂,而AKT/mTOR/ERK信号的抑制对于尿石素A诱导的口腔癌生长抑制至关重要.
结论：尿石素A通过诱导OSCC细胞凋亡和自噬途径发挥其抗肿瘤活性。我们的发现表明，尿石素A通过诱导内质网应激和随后的AKT和mTOR信号传导的抑制显着诱导口腔鳞状细胞癌的细胞死亡，磷酸化mTOR和4EBP1水平降低证明了这一点。尿石素A在体外和体内小鼠模型中均显着抑制肿瘤生长，表明其作为预防和治疗OSCC的抗癌剂的潜力。从今以后,我们的研究结果为尿石素A在预防和治疗OSCC方面的治疗潜力提供了新的见解.
