CNP mediated selective toxicity on melanoma cells is accompanied by mitochondrial dysfunction

Abstract

Cerium (Ce) oxide nanoparticles (CNP; nanoceria) are reported to have cytotoxic effects on certain cancerous cell lines, while at the same concentration they show no cytotoxicity on normal (healthy) cells. Redox-active CNP exhibit both selective prooxidative as well as antioxidative properties. The former is proposed to be responsible for impairment of tumor growth and invasion and the latter for rescuing normal cells from reactive oxygen species (ROS)-induced damage. Here we address possible underlying mechanisms of prooxidative effects of CNP in a metastatic human melanoma cell line. Malignant melanoma is the most aggressive form of skin cancer, and once it becomes metastatic the prognosis is very poor. We have shown earlier that CNP selectively kill A375 melanoma cells by increasing intracellular ROS levels, whose basic amount is significantly higher than in the normal (healthy) counterpart, the melanocytes. Here we show that CNP initiate a mitochondrial increase of ROS levels accompanied by an increase in mitochondrial thiol oxidation. Furthermore, we observed CNP-induced changes in mitochondrial bioenergetics, dynamics, and cristae morphology demonstrating mitochondrial dysfunction which finally led to tumor cell death. CNPinduced cell death is abolished by administration of PEG-conjugated catalase. Overall, we propose that cerium oxide nanoparticles mediate cell death via hydrogen peroxide production linked to mitochondrial dysfunction.

The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro

“…Since the cellular uptake of GP is similar in both A375 melanoma cells and NHEM melanocytes, the question rises why GP has a selective toxic effect on tumor cells. One explanation could be oxidative stress, since tumor cells have an increased basal ROS content compared to healthy cells and are, therefore, more susceptible to further ROS formation via, for example, nanoparticles or H 2 O 2 (Alili et al 2013 ; Aplak et al 2020 ). It has been reported that GP has a pro-oxidative effect in breast, pancreatic and prostate cancer (Zubair et al 2016 ) as well as in multiple myeloma (Xu et al 2014 ).…”

Bromodomain‐containing protein 4 inhibitor JQ1 promotes melanoma cell apoptosis by regulating mitochondrial dynamics

“… 38 Cerium oxide nanoparticles (CNP; nanoceria) have been reported to induce changes in dynamics that lead to mitochondrial dysfunction and eventually lead to melanoma cell death. 39 Soares et al demonstrated that increased MFN2 expression in melanoma is significantly positively correlated with lymph node involvement and distant metastasis. 40 In this study, we found that JQ1 treatment significantly increased the expression of mitochondrial fission proteins and decreased the expression of fusion proteins in B16 cells.…”

“…In melanoma, there is limited information regarding the role of mitochondrial dynamics in tumor progression and its effect on mitochondrial dysfunction 38 . Cerium oxide nanoparticles (CNP; nanoceria) have been reported to induce changes in dynamics that lead to mitochondrial dysfunction and eventually lead to melanoma cell death 39 . Soares et al demonstrated that increased MFN2 expression in melanoma is significantly positively correlated with lymph node involvement and distant metastasis 40 .…”

ROS as Regulators of Cellular Processes in Melanoma

“…The former mechanism is engaged by cerium (Ce) oxide nanoparticles (CNP; nanoceria) which selectively kills A375 melanoma cells through the increase of ROS concentration, prevalently hydrogen peroxide, at mitochondrial level. Such event occurs concomitantly to mitochondrial thiol oxidation and is followed by modifications in mitochondrial bioenergetics, dynamics, and cristae morphology, and ultimately by mitochondrial dysfunction-induced cell death [ 173 ]. Moreover, increased concentrations of ROS can reduce melanoma development through activation of cell cycle regulators and arrest of cell cycle in G2/M phase by the inhibition of Cdc25c and cyclin A [ 171 ].…”