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Page 2 of 11 Cote et al. J Cancer Metastasis Treat 2022;8:36 https://dx.doi.org/10.20517/2394-4722.2022.41

peritoneal mesothelial lining of the lungs and abdomen. Although asbestos exposure is a major risk factor
[1]
for the development of MM, little is known about the etiology of the disease . Similar to the majority of
other solid tumors, MM is strongly linked to altered metabolism, changes in mitochondrial dynamics and
an imbalance in the production and clearance of reactive oxygen species (ROS). Because of this, ROS
production and metabolism have become an exciting target for cancer treatments including MM .
[3]
[2]
Numerous approaches currently used in the clinic to treat MM, including cisplatin, have also been shown to
modulate ROS levels . Recently, thiostrepton (TS), an inhibitor of mitochondrial peroxiredoxin 3 that
[4]
induces elevated ROS levels and cell death , entered phase 1/2 clinical trials (NCT05278975), providing a
[5,6]
new and exciting redox-dependent therapy for the treatment of MM. This review will discuss the role of
ROS in cancer development and the unique mitochondrial dynamics and redox status in MM that may be
an effective target for anticancer therapies.

CANCER AND ROS
Ros in cell signaling
The role of ROS in normal and cancer cells is far more than just damaging or a byproduct of oxidative
metabolism. ROS contribute to cell signaling cascades through a process termed “redox-dependent
[7]
signaling” . ROS can directly or indirectly oxidize cysteine residues in proteins through hydrogen
[8]
peroxide (H O )-mediated oxidation of target proteins or through peroxiredoxin (Prx)-dependent redox
2
2
relays . ROS are produced by intracellular and extracellular sources, including asbestos, and dynamically
[9]
regulate numerous cell signaling pathways . Intracellular sources of ROS, such as NADPH oxidases and
[10]
the mitochondrial electron transport chain, participate in redox-dependent signaling spatially and
temporally [11,12] [Figure 1]. Control over the amount, timing and location of ROS contributes to specific
redox signaling events, akin to cellular control over protein phosphorylation cascades . One well-known
[13]
redox signaling event is in the cell’s response to hypoxia, which is mediated by the stabilization of hypoxia-
inducible factors (HIFs). Under normal conditions, prolyl hydroxylase domain protein 2 (PHD2) prevents
HIF stabilization by hydroxylating two of its proline residues, marking it for degradation . PHD2 is
[14]
deactivated at low oxygen levels, allowing HIF stabilization. A study performed by Chandel et al. found that
the production of mROS was required for HIF stabilization under hypoxia, though the mechanism is still
unclear [15,16] . In cancer cells, HIF stabilization stimulates angiogenesis, glycolysis, and cell survival, key
hallmarks of tumorigenesis .
[2]

ROS IN TUMORIGENESIS AND TUMOR CELL RESPONCE TO ROS
The increased production of ROS in tumor cells is described as a “double-edged sword” in the process of
[17]
[18]
tumorigenesis . Increased ROS, often driven by oncogene activation , must be managed by cancer cells
by upregulating various antioxidant networks, as excessive oxidative stress would normally induce
senescence and/or apoptosis in cells [Figure 1]. Conversely, ROS is also thought to promote cell
[19]
proliferation by inducing DNA mutations and activating redox-dependent signaling pathways . One
[17]
specific way ROS may promote tumorigenesis is by activating the phosphoinositide 3-kinase (PI3K)
pathway. This pathway is upregulated in cancer cells and promotes cell proliferation, survival, and
mobility . It is also known that ROS inhibits phosphatase and tensin homolog (PTEN) activity, which
[20]
allows for constitutive expression of PI3K when inactivated [21,22] [Figure 1]. Increased ROS levels in human
MM cells enhance the expression of the oncogenic transcription factor FOXM1 which supports cell cycle
progression and escape from oxidative stress [23-25] [Figure 1]. ROS also have the ability to alter metabolism,
an example of which is by oxidation of key cysteine residues in pyruvate kinase M2 (PKM2). The oxidation
358
of Cys on PKM2 is thought to increase pentose phosphate pathway flux and cell proliferation in hypoxic
[26]
conditions . Inhibition of PKM2 has been associated with increased tumorigenesis [27,28] .