Cytoglobin protects cancer cells from apoptosis by regulation of mitochondrial cardiolipin

Abstract

Cytoglobin is important in the progression of oral squamous cell carcinoma but the molecular and cellular basis remain to be elucidated. In the current study, we develop a new cell model to study the function of cytoglobin in oral squamous carcinoma and response to cisplatin. Transcriptomic profiling showed cytoglobin mediated changes in expression of genes related to stress response, redox metabolism, mitochondrial function, cell adhesion, and fatty acid metabolism. Cellular and biochemical studies show that cytoglobin expression results in changes to phenotype associated with cancer progression including: increased cellular proliferation, motility and cell cycle progression. Cytoglobin also protects cells from cisplatin-induced apoptosis and oxidative stress with levels of the antioxidant glutathione increased and total and mitochondrial reactive oxygen species levels reduced. The mechanism of cisplatin resistance involved inhibition of caspase 9 activation and cytoglobin protected mitochondria from oxidative stress-induced fission. To understand the mechanism behind these phenotypic changes we employed lipidomic analysis and demonstrate that levels of the redox sensitive and apoptosis regulating cardiolipin are significantly up-regulated in cells expressing cytoglobin. In conclusion, our data shows that cytoglobin expression results in important phenotypic changes that could be exploited by cancer cells in vivo to facilitate disease progression.

Cytoglobin inhibits non-thermal plasma-induced apoptosis in melanoma cells through regulation of the NRF2-mediated antioxidant response

“…Yet, in G361-shCYGB cells, NRF2 and HO-1 levels were reduced by half, which could potentially have a large biological impact. This is in accordance with other studies that showed a downregulation of antioxidant enzymes or a dysregulation of the NRF2 pathway upon loss of CYGB [ 24 , [64] , [65] , [66] ].…”

Cytoglobin Silencing Promotes Melanoma Malignancy but Sensitizes for Ferroptosis and Pyroptosis Therapy Response

“…Intriguingly, the knockdown of CYGB also affected NRF2 and HO-1 protein expression under basal conditions ( Figure S3 ). This is in accordance with previous studies [ 14 , 39 , 40 , 41 ] and is consistent with results obtained recently by our group [ 31 ]. Considering NRF2’s central role in heme biosynthesis, and taking into account CYGB as a heme-containing protein, cells possessing abundant endogenous CYGB levels constitutively induce NRF2 protein, and subsequently HO-1 [ 42 , 43 ].…”

“…However, cardiolipin (CL) was shown to be necessary for NLRP3 inflammasome activation [ 72 ]. As CYGB can interact with and regulate the redox status of CL [ 41 , 73 ], CYGB could indirectly regulate pyroptotic cell death.…”

Reactive Oxygen Species: Not Omnipresent but Important in Many Locations

“…This further places the model of ROS molecules, which “flood” the whole cell from a single location of ROS production in rather unrealistic light. Nevertheless, the model of ROS as “flooding” the cell is still popular in the scientific community, often referred to as “total cellular ROS levels” ( Wang et al, 2013 , 2019 ; Dinakar et al, 2016 ; Kim and Xue, 2020 ; Loth et al, 2020 ; Thorne et al, 2021 ), “intracellular ROS levels” ( Tepel et al, 2000 ; Bensaad et al, 2009 ; Choi et al, 2011 ; Lee et al, 2017 ; Wang et al, 2019 , 2021a ; Wei et al, 2019 ; Zaidieh et al, 2019 ; Zhang W. et al, 2019 ; Mendiola et al, 2020 ; Winitchaikul et al, 2021 ; Zhong et al, 2021 ) or simply “ROS levels” ( Chen et al, 2012 , 2021 ; Wei et al, 2019 ; Agarwal and Ganesh, 2020 ; Kim et al, 2021 ; Knight et al, 2021 ; Zeller et al, 2021 ) in many studies, mainly because of the usage of diffusible ROS probes, which suggest free diffusion of ROS through the cell without regard of the location of ROS production. Mutations, e.g., in cancer cells ( Schumacker, 2006 ; Liou and Storz, 2010 ; Reczek and Chandel, 2017 ; Zaidieh et al, 2019 ; Perillo et al, 2020 ), pathogenic invasion ( West et al, 2011a ; Abuaita et al, 2018 ; Gluschko et al, 2018 ; Roca et al, 2019 ) or metabolic disbalance ( Li et al, 2016 ; Mak et al, 2017 ; Peng et al, 2021 ) are prominent examples, in which the ROS production of the cell can enter an uncontrolled stage and quickly overcome the antioxidative defense system leading to rapidly increased ROS levels in nearly every compartment of the cell with often detrimental consequences.…”