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Page 4 of 40 Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60

Figure 1. Sonic hedgehog signaling pathway. This figure describes the genetic signaling pathway of SHH. SHH: sonic hedgehog; SMO:
smoothened

of cells with damaged DNA. On the other hand, ATR and ATM can directly phosphorylate E3 ubiquitin
ligase SIAH1 which activates p53. The activation of p53 sends cells that normally should be permitted to
proliferate to go into apoptosis. Thus, the dysregulation of ATR and ATM results in unpredictable cell cycle
activity, especially at the p53 checkpoint which is known as “the guardian of the genome”.

Apoptosis evasion
Role of UV
UV exposure activates stress responses in the epidermis such as reactive oxygen species production which
damages lipids, proteins, and DNA while also invoking antioxidant defense by suppressing tumorigenesis
[27]
and initiating apoptotic pathways . The conflicting evidence forces the consideration that antioxidative
therapies may be counterintuitive in the treatment of certain cancers. When observing the tumors of
melanoma and non-melanoma patients, NMSC had lower levels of superoxide dismutase and catalase when
compared to the melanoma samples. This observation suggests that NMSC are associated with weaker
[28]
antioxidative defenses during tumorigenesis . To examine the signaling involved in oxidative stress, we
will explore the p38 mitogen-activated protein kinases (p38) and c-Jun N-terminal kinases (JNK) pathways,
both of which have been shown to be involved in pro- and anti-apoptotic mechanisms .
[29]

P38 signaling
P38 is a Raf-mitogen activated protein kinase (MAPK) protein that can respond to oxidative stress by
triggering apoptosis. When oxidative stress activates the p38 system in keratinocytes, apoptosis signal-
[30]
regulating kinase 1 may become activated . Oxidative stress also inhibits MAPK phosphatases resulting in
[31]
increased p38 activation . UV alone suffices in activating the p38 signaling pathway [30,32] .
JNK signaling
JNK is another member of the MAPK family that can be activated in as little as 5 min post-UV exposure.
JNK targets activator protein-1 (AP-1) which is an oncogenic transcription factor involved in cell cycle
[33]
regulation . Although associated with pro-apoptotic activity, AP-1 can promote survival through crosstalk
with the NF-kB pathway. Pharmacological studies have shown that the inhibition of JNK in human
[34]
keratinocytes in vitro results in greater UV-induced apoptosis . The same effect was shown in vivo when
[35]
inhibiting AP-1 in dominant negative c-jun hairless mice .