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Page 10 of 15 Girotti et al. J Cancer Metastasis Treat 2020;6:52 I http://dx.doi.org/10.20517/2394-4722.2020.107

Figure 5. Photostress-induced upstream signaling events leading ultimately to iNOS transcriptional upregulation. Key effectors
(LY294002, C646) and their protein targets. ALA: 5-Aminolevulinic acid; NO: nitric oxide; iNOS: inducible NO synthase; hν: irradiation;
1
O 2 : photogenerated singlet oxygen; LOOH: hydroperoxide of mitochondrial membrane lipids; PTEN: phosphatase and tensin homologue;
PIP3: phosphatidylisositol-3,4,5-triphosphate; PIP2: phosphatidylinositol 4, 5-bisphosphate; PI3K: phosphoinositide 3-kinase; PDK1:
3-Phosphoinositide-dependent protein kinase-1; p-Akt: phosphorylated Akt; p-p300: phosphorylation-activated p300; Sirt1: sirtuin 1;
Brd4: bromodomain-containing protein 4; NO: nitric oxide; iNOS: inducible NO synthase (Reproduced from Ref. 59, with permission)
reaction, reversible NO reactions can also take place and fall into the signaling category. A well-known
example is protein S-nitrosation, i.e., reaction of specialized cysteine thiol groups with NO (or more likely
[57]
[71]
NO-derived N O ) to give S-nitroso (SNO) adducts . Except for a conference report in 2002 , no solid
3
2
evidence for SNO formation in the context of PDT has been reported thus far. In contrast, several effector
proteins have been reported to undergo S-nitrosation in non-photodynamic systems, including: (1)
mitogen-activated protein kinases (MAPKs) such as ASK-1 and Jun-N-terminal kinase (JNK), whose pro-
[72]
[73]
apoptotic activities are inhibited ; (2) caspase-9, whose pro-apoptotic activation or activity is inhibited ;
[74]
(3) anti-apoptotic Bcl-2, whose ubiquitination and proteosomal degradation are inhibited ; and (4) anti-
apoptotic MAPK phosphatase-1 (MKP-1), whose proteosomal degradation is also inhibited . Protein
[75]
S-nitrosation can be monitored by mass spectrometry, but analysis is complex and the modification is
[76]
often transient due to thioredoxin-mediated denitrosation . In the case of PDT, the latter could occur at
some point after photostress is incurred, so optimal timing of cell or tissue analysis after irradiation poses a
challenge.
BYSTANDER EFFECTS OF PDT-UPREGULATED INOS/NO
Most advanced tumors, including glioblastomas, have a limited vascular supply, and, because of this,
not all tumor cells will be uniformly accessed by an active PS or pro-PS such as ALA. Moreover, during
subsequent irradiation, some cells will be less exposed than others due to light field limits, variable
tumor geometry, and other complex factors. Thus, it is conceivable that cells experiencing the greatest
photodynamic stress might respond to it by sending signals to non- or weakly-stressed neighboring cells,