Activation of Dioxin Receptor in Skin Cancer (Photocarcinogenesis)

-In a presentation about psoriasis, the beneficial effect of the sun is suggested by being due to sunlight (UV) stimulationg the synthesis of molecules linking to AhR (Aryl Hydrocarbon receptor also known as dioxin receptor).
-These AhR ligands are synthesized from tryptophan.

A word on AhR
AhR is also known as dioxin receptor and acts as a sensor of the environment :
-it is an intracellular receptor (in the cytosol)
-upon ligand-binding, it translocates into the nucleus to activate DNA transcription with the help of AhR responsive elements goes into the nucleus to activate transcription
-transcripted and expresses genes include AhR, CypA1A, CypA12 and  Cyp1B1 (apoptosis and proliferation)

Absorption of Tryptophane by UVB results in:
-sunburn
-immunosuppression
-skin cancer

UVB radiation causes generation of of CPDs (cyclobutane pyrimidine dimers) which causes cell cycle arrest in order to undergo apoptosis if the damage is too high, or to repair (nucleotide excision repair)…when deregulated it can give rise to skin cancers (photocarcinogenesis)

AHR sensitizes keratinocytes to UVB-inducesd apoptosis in normal keratinocytes:

• there is a UVB-induced cleavage of PARP1 (marker of apoptosis)
• With AhR agonists: there is decreased apoptosis; in other words, the cell survives in  instead of undergoing apoptosis and can degenerate into a malignant keratinocyte (or repair)
• Similar results are seen in keratinocytes coming from Squamous Cell Carcinoma (SCC) lesions

Remarks
–CHK checkpoint kinase 1 is increased with UVB and reduces apoptosis; this enables cell survival. (In AhR knockout cells, loss of E2F1 in AhR negative cells reduces CHK1 levels).
–AHR receptor is an apoptotic molecule (indeed in AhR knockout mice there is an increase in caspase 3, which is a marker of apoptosis)
–52% of AhR knockout mice develop UV-induced cutaneous SCCs

Conclusion
-AhR could be used as a target by linking it to an antagonist.
-BDDI is an AhR antagonist suitable for topical application in humans

Comments
-We do not have a positive view of tobacco smoke extracts, but they also stimulate AhR. However extracts from tobacco smoke cause photoaging by activating metalloproteinases through the AhR pathway (click HERE to read more)

Prevention of photocarciogenesis by targeting the AhR. Thomas Haarmann-Stemmann (Germany). SY16 – Photoprotection and Sunscreens. World Congress of Dermatology 2015 –  Vancouver, Canada