Faris Pawan, Rumolo Agnese, Pellavio Giorgia, Tanzi Matteo, Vismara Mauro, Berra-Romani Roberto, Gerbino Andrea, Corallo Salvatore, Pedrazzoli Paolo, Laforenza Umberto, Montagna Daniela, Moccia Francesco
Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, via Forlanini 6, 27100, Pavia, Italy.
Foundation IRCCS Policlinico San Matteo, Laboratory of Immunology Transplantation, Piazzale Golgi 19, Pavia, Italy.
Cell Death Discov. 2023 Jul 1;9(1):213. doi: 10.1038/s41420-023-01530-x.
Colorectal carcinoma (CRC) represents the fourth most common cancer worldwide and is the third most common cause of malignancy-associated mortality. Distant metastases to the liver and lungs are the main drivers of CRC-dependent death. Pro-oxidant therapies, which halt disease progression by exacerbating oxidative stress, represent an antitumour strategy that is currently exploited by chemotherapy and ionizing radiation. A more selective strategy to therapeutically exploit reactive oxygen species (ROS) signaling would consist in targeting a redox sensor that is up-regulated in metastatic cells and is tightly coupled to the stimulation of cancer cell death programs. The non-selective cation channel, Transient Receptor Potential Ankyrin 1 (TRPA1), serves as a sensor of the cellular redox state, being activated to promote extracellular Ca entry by an increase in oxidative stress. Recent work demonstrated that TRPA1 channel protein is up-regulated in several cancer types and that TRPA1-mediated Ca signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca dysfunction and apoptosis. Herein, we sought to assess for the first time the outcome of TRPA1 activation by ROS on primary cultures of metastatic colorectal carcinoma (mCRC cells). We found that TRPA1 channel protein is up-regulated and mediates enhanced hydrogen peroxide (HO)-induced Ca entry in mCRC cells as compared to non-neoplastic control cells. The lipid peroxidation product 4-hydroxynonenal (4-HNE) is the main ROS responsible for TRPA1 activation upon mCRC cell exposure to oxidative stress. TRPA1-mediated Ca entry in response to HO and 4-HNE results in mitochondrial Ca overload, followed by mitochondrial depolarization and caspase-3/7 activation. Therefore, targeting TRPA1 could represent an alternative strategy to eradicate metastatic CRC by enhancing its sensitivity to oxidative stress.
结直肠癌（CRC）是全球第四大常见癌症，也是恶性肿瘤相关死亡的第三大常见原因。肝和肺的远处转移是CRC相关死亡的主要驱动因素。促氧化疗法通过加剧氧化应激来阻止疾病进展，是目前化疗和电离辐射所采用的一种抗肿瘤策略。一种更具选择性的利用活性氧（ROS）信号进行治疗的策略是靶向一种在转移细胞中上调且与癌细胞死亡程序刺激紧密相关的氧化还原传感器。非选择性阳离子通道瞬时受体电位锚蛋白1（TRPA1）作为细胞氧化还原状态的传感器，在氧化应激增加时被激活以促进细胞外钙内流。最近的研究表明，TRPA1通道蛋白在几种癌症类型中上调，并且TRPA1介导的钙信号既可以参与抗凋亡的促生存信号通路，也可以促进线粒体钙功能障碍和凋亡。在此，我们首次试图评估ROS激活TRPA1对转移性结直肠癌原代培养物（mCRC细胞）的影响。我们发现，与非肿瘤对照细胞相比，TRPA1通道蛋白在mCRC细胞中上调，并介导过氧化氢（H₂O₂）诱导的钙内流增强。脂质过氧化产物4-羟基壬烯醛（4-HNE）是mCRC细胞暴露于氧化应激时激活TRPA1的主要ROS。TRPA1介导的对H₂O₂和4-HNE的钙内流导致线粒体钙超载，随后线粒体去极化和半胱天冬酶-3/7激活。因此，靶向TRPA1可能是一种通过增强转移性CRC对氧化应激的敏感性来根除它的替代策略。
