Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing

doi:10.3390/cancers13205062

	Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing
	Nardin, Chiara 1; Peres, Chiara 1; Putti, Sabrina 1; Orsini, Tiziana 1; Colussi, Claudia 2,3; Mazzarda, Flavia 1,4; Raspa, Marcello 1; Scavizzi, Ferdinando 1; Salvatore, Anna Maria 1; Chiani, Francesco 1; Tettey-Matey, Abraham 1; Kuang, Yuanyuan5 ; Yang, Guang5 ; Retamal, Mauricio A.6; Mammano, Fabio 1,7
	2021
发表期刊	CANCERS (IF:4.5[JCR-2023],4.9[5-Year])
EISSN	2072-6694
卷号	13 期号:20
DOI	10.3390/cancers13205062
摘要	Simple Summary Bystander effects depend on direct cell-cell communication and/or paracrine signaling mediated by the release of soluble factors into the extracellular environment and may greatly influence therapy outcome. Although the limited data available suggest a role for intercellular gap junction channels, far less is known about the role of connexin hemichannels. Here, we investigated bystander effects induced by photodynamic therapy in syngeneic murine melanoma models in vivo. We determined that (i) photoactivation of a photosensitizer triggered calcium-dependent cell death pathways in both irradiated and bystander tumor cells; (ii) hemichannel activity and adenosine triphosphate release were key factors for the induction of bystander cell death; and (iii) bystander cell killing and antitumor response elicited by photodynamic therapy were greatly enhanced by combination treatment with S-nitrosoglutathione, which promoted hemichannel opening in these experimental conditions. Therefore, these findings in a preclinical model have important translational potential. In this study, we used B16-F10 cells grown in the dorsal skinfold chamber (DSC) preparation that allowed us to gain optical access to the processes triggered by photodynamic therapy (PDT). Partial irradiation of a photosensitized melanoma triggered cell death in non-irradiated tumor cells. Multiphoton intravital microscopy with genetically encoded fluorescence indicators revealed that bystander cell death was mediated by paracrine signaling due to adenosine triphosphate (ATP) release from connexin (Cx) hemichannels (HCs). Intercellular calcium (Ca2+) waves propagated from irradiated to bystander cells promoting intracellular Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria and rapid activation of apoptotic pathways. Combination treatment with S-nitrosoglutathione (GSNO), an endogenous nitric oxide (NO) donor that biases HCs towards the open state, greatly potentiated anti-tumor bystander killing via enhanced Ca2+ signaling, leading to a significant reduction of post-irradiation tumor mass. Our results demonstrate that HCs can be exploited to dramatically increase cytotoxic bystander effects and reveal a previously unappreciated role for HCs in tumor eradication promoted by PDT.
关键词	photosensitization nitric oxide purinergic signaling calcium signaling
URL	查看原文
收录类别	SCIE
语种	英语
WOS研究方向	Oncology
WOS类目	Oncology
WOS记录号	WOS:000714877900001
出版者	MDPI
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/130328
专题	生命科学与技术学院_博士生免疫化学研究所_特聘教授组_功能筛选实验室
通讯作者	Mammano, Fabio
作者单位	1.CNR, Inst Biochem & Cell Biol IBBC, I-00015 Rome, Italy; 2.CNR, Inst Syst Anal & Comp Sci A Ruberti IASI, I-00168 Rome, Italy; 3.Univ Cattolica Sacro Cuore, Fdn Policlin Univ Agostino Gemelli IRCCS, I-00168 Rome, Italy; 4.Old Dominion Univ, Frank Reidy Res Ctr Bioelect, Norfolk, VA 23508 USA; 5.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China; 6.Univ Desarrollo, Ctr Fisiol Celular & Integrat, Fac Med Clin Alemana, Santiago 7780272, Chile; 7.Univ Padua, Dept Phys & Astron G Galilei, I-35131 Padua, Italy
推荐引用方式 GB/T 7714	Nardin, Chiara,Peres, Chiara,Putti, Sabrina,et al. Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing[J]. CANCERS,2021,13(20).
APA	Nardin, Chiara.,Peres, Chiara.,Putti, Sabrina.,Orsini, Tiziana.,Colussi, Claudia.,...&Mammano, Fabio.(2021).Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing.CANCERS,13(20).
MLA	Nardin, Chiara,et al."Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing".CANCERS 13.20(2021).