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Page 4 of 11 Cote et al. J Cancer Metastasis Treat 2022;8:36 https://dx.doi.org/10.20517/2394-4722.2022.41

Interestingly, p53, although mutated in many forms of cancer, is almost always a wild type in MM cell lines.
[40]
Its function, however, is usually inhibited by other gene deletions frequently found in MM cells .
ROS IN MALIGNANT MESOTHELIOMA
Human MM cell lines demonstrate elevated levels of antioxidant enzymes such as manganese superoxide
[41]
dismutase (MnSOD) , peroxiredoxins (PRXs) and the mitochondrial thioredoxin reductase 2 (TrxR2) -
[42]
thioredoxin 2 (Trx2) - peroxiredoxin 3 (Prx3) antioxidant network compared to normal mesothelial cells.
[43]
The upregulation of MnSOD is significant as it is the only antioxidant induced by asbestos exposure and
contributes to the high resistance to oxidant chemotherapeutic drugs displayed by MM cells . MM cells
[44]
also display increased expression of many PRXs , a family of H O scavenging enzymes found in the
[45]
2
2
cytoplasm (PRX1, PRX2), mitochondria (PRX3, PRX5) and endoplasmic reticulum (PRX4). Some members
have notable functions, such as PRX2, which induces cell proliferation and protects cells from undergoing
[47]
oxidative stress-induced apoptosis . PRX3 protects tumor cells from apoptosis and knockdown of PRX3
[46]
in human MM cells leads to reduced proliferation and altered cell cycle progression [5,23] . The role of PRX3 in
cancer is still being uncovered, but its importance in maintaining mitochondrial redox status is clear as
[48]
PRX3 is estimated to metabolize ~90% of mitochondrial H O . Targeting PRX3 for the treatment of MM
2
2
is a new avenue being explored in clinical trials (elaborated below).
Disruption of cellular redox status via depletion of glutathione (GSH) and iron-dependent lipid oxidation
contributes to a type of programmed cell death termed ferroptosis . Inactivation of NF2, LATS1, or
[49]
LATS2, genes involved in signaling cascades that prevent ferroptosis, are recently identified mutations in
MM cells that sensitize them to ferroptosis . Approaches to targeting these mutations and taking
[50]
advantage of this ferroptosis sensitivity, as well as looking into other possible pathways involved in
ferroptosis, are an avenue for therapeutic intervention in MM. One proposed target is BAP1, the most
commonly mutated gene in MM, which can inhibit ferroptosis when mutated [51,52] . Interestingly, fibroblasts
harboring heterozygous BAP1 mutations show altered metabolite profiles and mitochondrial respiration,
including reduced citric acid cycle metabolites and mitochondrial oxygen consumption . It was concluded
[53]
that BAP1 mutant fibroblasts are preferentially undergoing aerobic glycolysis (Warburg effect). Additional
studies in a mesothelioma cell line (NCI-H226), which does not express BAP1, showed that reconstitution
of BAP1 into these cell lines promoted ROS production, gene-expression changes indicative of increased
cellular oxidative stress and increased sensitivity to exogenous H O [Figure 1]. These results provide a
[54]
2
2
path forward for looking into BAP1 status in the context of redox-dependent therapies.
FOX protein family members, including FOXM1, are thought to mediate tumorigenesis and promote the
survival of MM cells . High FOXM1 expression is found in MM cells, and tumors and knockdown of
[24]
FOXM1 with siRNA slows the growth of MM cells [55,56] . FOXM1 also regulates the expression of genes
involved in cell survival and cell cycle progression. The two oncogenic isoforms of the protein, FOXM1B
and FOXM1C, act as transcriptional activators and are both upregulated in MM cancer cells, suggesting that
FOXM1 may be a viable target for cancer treatment [24,57] . The expression of FOXM1 is induced by the
production of H O 2 [25,58] . FOXM1 counteracts oxidative stress by upregulating the expression of antioxidant
2
enzymes such as SODs, catalase, and PRX3, which suppresses oncogene-induced senescence and supports
tumor cell growth [Figure 1]. PRX3 functions by metabolizing H O , which causes catalytic cysteine
[25]
2
2
residues in PRX3 to form a disulfide bond. This bond is reduced by thioredoxin 2 (TRX2), regenerating
PRX3 to its active conformation and able to metabolize another molecule of H O . TRX2 is subsequently
[59]
2
2
[60]
regenerated by TR2 using NADPH as the reductant . Notably, TR2 and TRX2 are also upregulated in
cancer cells, and measuring the activity of TR2 is proposed to be a useful way to monitor the growth of MM
[61]
cell lines . The TR2-TRX2-PRX3 system has been identified as a pathway for therapeutic intervention in