The TRPA1 Channel Amplifies the Oxidative Stress Signal in Melanoma

Logu, Francesco De; Araújo, Daniel Souza Monteiro de; Ugolini, Filippo; Iannone, Luigi Francesco; Vannucchi, Margherita; Portelli, Francesca; Landini, Lorenzo; Titiz, Mustafa; Giorgi, Vincenzo De; Geppetti, Pierangelo; Massi, Daniela; Nassini, Romina

doi:10.3390/cells10113131

Cited by 13 publications

(18 citation statements)

References 61 publications

(103 reference statements)

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“…3E , F ) [ 26 , 28 ]. Oxidative stress in cancer microenvironment may result in the peroxidation of ω6 polyunsaturated fatty acids in the plasma membrane, thereby leading to the formation of 4-hydroxy-nonenal (4-HNE) [ 9 , 29 ]. 4-HNE has recently been shown to stimulate TRPA1-mediated Ca 2+ influx in several cell types [ 30 , 31 ], including melanoma cell lines [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells

et al. 2023

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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 Ca2+ 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 Ca2+ signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca2+ 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 (H2O2)-induced Ca2+ 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 Ca2+ entry in response to H2O2 and 4-HNE results in mitochondrial Ca2+ 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.

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Section: Resultsmentioning

confidence: 99%

Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells

et al. 2023

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“…There is strong evidence that oxidative aldehydes, such as 4-hydroxy-2E-nonenal (4-HNE), activate TRPA1 through covalent modification of cysteine and lysine residues located within the amino-terminal cytoplasmic domain of the channel ( 13 , 49 , 50 ), and that 4-HNE activation of TRPA1 mediates inflammatory and neuropathic pain ( 12 , 13 ). Furthermore, TRPA1 activation by H 2 O 2 has been shown to evoke additional H 2 O 2 release in melanoma cell lines that further amplify the oxidative stress ( 51 ). Therefore, ROS and TRPA1 interactions in any stage of nociceptive processing can lead to sensitization of neurons, promoting pain hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Intraganglionic reactive oxygen species mediate inflammatory pain and hyperalgesia through TRPA1 in the rat

et al. 2023

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Reactive oxygen species (ROS) are generated in nociceptive pathways in response to inflammation and injury. ROS are accumulated within the sensory ganglia following peripheral inflammation, but the functional role of intraganlionic ROS in inflammatory pain is not clearly understood. The aims of this study were to investigate whether peripheral inflammation leads to prolonged ROS accumulation within the trigeminal ganglia (TG), whether intraganglionic ROS mediate pain hypersensitivity via activation of TRPA1, and whether TRPA1 expression is upregulated in TG during inflammatory conditions by ROS. We demonstrated that peripheral inflammation causes excess ROS production within TG during the period when inflammatory mechanical hyperalgesia is most prominent. Additionally, scavenging intraganglionic ROS attenuated inflammatory mechanical hyperalgesia and a pharmacological blockade of TRPA1 localized within TG also mitigated inflammatory mechanical hyperalgesia. Interestingly, exogenous administration of ROS into TG elicited mechanical hyperalgesia and spontaneous pain-like responses via TRPA1, and intraganglionic ROS induced TRPA1 upregulation in TG. These results collectively suggest that ROS accumulation in TG during peripheral inflammation contributes to pain and hyperalgesia in a TRPA1 dependent manner, and that ROS further exacerbate pathological pain responses by upregulating TRPA1 expression. Therefore, any conditions that exacerbate ROS accumulation within somatic sensory ganglia can aggravate pain responses and treatments reducing ganglionic ROS may help alleviate inflammatory pain.

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“…The TRPA1 expression was reported in melanoma cell lines. De Logu et al assessed the infiltration and state of macrophages, 4-HNE, a final end-product of oxidative stress, and the TRPA1 expression in tissue samples of human common dermal melanocytic nevi, dysplastic nevi, and thin and thick cutaneous melanomas [10]. The number of CD163-positive M2-type macrophages and the 4-HNE level in the intratumoural and peritumoural regions progressively increased with tumour severity, but the TRPA1 expression was not altered.…”

Section: Cutaneous Melanomamentioning

confidence: 99%