Lou Yantao, Ma Chunlei, Liu Zhifei, Shi Jianxi, Zheng Guangzhe, Zhang Changwen, Zhang Zhihong
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
Ecotoxicol Environ Saf. 2021 Sep 15;221:112420. doi: 10.1016/j.ecoenv.2021.112420. Epub 2021 Jun 21.
Antimony is one of the heavier pnictogens and is widely found in human food chains, water sources, and as an air pollutant. Recent years have seen steadily increasing concentrations of antimony in the ecological environment; critically, several studies have indicated that antimony might pose a tumorigenic risk factor in several cancers. Therefore, antimony toxicity has attracted increasing research attention, with the molecular mechanisms underlying suspected antimony-mediated tumor transformation of greatest interest. Our results showed that the serum concentration of antimony was higher in bladder tumor patients relative to levels in non-tumor patients. Moreover, that such high antimony serum concentration were closely associated with poorer outcome in bladder tumor patients. Additionally, we demonstrated that the presence of antimony promoted both in vitro and in vivo bladder tumor cell growth. Our results also indicated that low-dose antimony resulted in significantly decreased mitochondrial membrane potential, mitochondrial respiratory enzyme complex I/II/III/IV activity, ATP/ADP ratio, and ATP concentration relative to the control group. These findings suggested that antimony caused mitochondrial damage. Finally, we found that low-dose antimony(0.8uM) inhibited mitophagy by deregulating expression of PINK1, Parkin, and p(ser65)-Parkin, and activation of PINK1-Parkin pathway by CCCP could inhibit antimony-induced tumor cell growth. Collectively, this inhibited the proliferation of bladder tumor cells. Overall, our study suggested that antimony promoted bladder tumor cell growth by inhibiting PINK1-Parkin-mediated mitophagy. These findings highlight the therapeutic potential in targeting molecules within this antimony induced-PINK1/Parkin signaling pathway and may offer a new approach for the treatment of bladder cancer.
锑是较重的氮族元素之一，广泛存在于人类食物链、水源中，并作为空气污染物存在。近年来，生态环境中锑的浓度持续上升；至关重要的是，多项研究表明，锑可能是多种癌症的致瘤风险因素。因此，锑毒性已引起越来越多的研究关注，其中怀疑锑介导的肿瘤转化的分子机制最受关注。我们的结果表明，膀胱肿瘤患者血清中的锑浓度高于非肿瘤患者。此外，如此高的锑血清浓度与膀胱肿瘤患者较差的预后密切相关。此外，我们证明了锑的存在促进了体外和体内膀胱肿瘤细胞的生长。我们的结果还表明，与对照组相比，低剂量锑导致线粒体膜电位、线粒体呼吸酶复合物I/II/III/IV活性、ATP/ADP比率和ATP浓度显著降低。这些发现表明锑会导致线粒体损伤。最后，我们发现低剂量锑（0.8uM）通过失调PINK1、Parkin和p（ser65）-Parkin的表达抑制线粒体自噬，而CCCP激活PINK1-Parkin途径可抑制锑诱导的肿瘤细胞生长。总的来说，这抑制了膀胱肿瘤细胞的增殖。总体而言，我们的研究表明，锑通过抑制PINK1-Parkin介导的线粒体自噬促进膀胱肿瘤细胞生长。这些发现突出了靶向该锑诱导的PINK1/Parkin信号通路中分子的治疗潜力，并可能为膀胱癌的治疗提供一种新方法。
