Chemical carcinogenesis - receptor activation
This KEGG map shows how chemicals in tobacco smoke, industrial pollutants, plastics and hormones cause cancer without directly damaging DNA: they switch on receptors that drive growth signalling. It matters because these routes explain part of the cancer burden from smoking, dioxins and hormone exposure, and several of the receptors are druggable.
Overview
KEGG map hsa05207 covers the non-genotoxic arm of chemical carcinogenesis. Carcinogenesis proceeds through initiation, promotion and progression, and chemicals can act at any stage. Genotoxic agents damage DNA directly; non-genotoxic agents instead activate receptors. The map draws two receptor classes. Cell-surface receptors and some intracellular receptors trigger signal transduction: nicotine and the tobacco nitrosamines NNK and NNN act on nicotinic acetylcholine receptors and beta-adrenergic receptors to drive RAS-ERK, PI3K-AKT, JAK-STAT and cAMP signalling; bisphenol A and oestradiol act through membrane oestrogen receptors to RAS-ERK; arsenic feeds PI3K signalling; progesterone and medroxyprogesterone act through membrane and nuclear progesterone receptors. Nuclear receptors that translocate and act as transcription factors form the second class: oestradiol on the oestrogen receptor, and the aryl hydrocarbon receptor (AhR) activated by dioxin (TCDD), benzo[a]pyrene, polychlorinated biphenyls and hexachlorobenzene, which induces CYP1A1 and CYP1B1 and alters proliferation and immune genes.
Murray, Patterson and Perdew, Nature Reviews Cancer, 2014 (doi:10.1038/nrc3846) review the AhR arm: AhR ligands can promote tumours by inducing metabolic enzymes that activate pro-carcinogens, by crosstalk with oestrogen receptor and growth factor signalling, and by suppressing anti-tumour immunity, while in other contexts AhR agonists suppress tumour growth, hence the title's friend and foe.
What can be done: avoidance is the main lever (tobacco control, dioxin and PCB limits). Where the receptor is an established cancer driver the drugs already exist: endocrine therapy against the oestrogen receptor (tamoxifen, fulvestrant, aromatase inhibitors) and the androgen receptor (enzalutamide, abiraterone), and inhibitors of the downstream RAS-ERK and PI3K-AKT routes. AhR antagonists have been tested in early trials as immunotherapy sensitisers but none is approved.
In one picture
A doorbell that rings the growth alarm inside the cell. DNA-damaging carcinogens smash the wiring; the chemicals on this map instead stand outside pressing the bell over and over. Nicotine, dioxin, plastic additives and hormones each press a different bell, but the alarms all wire into the same growth circuits.
Diagram
top- Prevention first: tobacco control and limits on dioxin, PCB and bisphenol exposure remove the ligands
- Endocrine therapy against hormone receptors that these chemicals activate: tamoxifen, fulvestrant, elacestrant and aromatase inhibitors (letrozole) for ER; enzalutamide and abiraterone for AR
- Inhibitors of the downstream growth routes: MEK inhibitors, PI3K/AKT inhibitors (alpelisib, capivasertib)
- Aryl hydrocarbon receptor antagonists as immunotherapy sensitisers (early clinical trials, none approved)
Pages like this
not linked directly; found by shared links- PairingPI3K/AKT-pathway inhibitor + endocrine therapy (± CDK4/6)
Shares Alpelisib, Fulvestrant, Capivasertib, PIK3CA / PI3K-alpha.
- PathwayBreast cancer (KEGG map)
Shares Alpelisib, Fulvestrant, Elacestrant, Capivasertib.
- PathwayMicroRNAs in cancer
Shares Alpelisib, Capivasertib, p53 / RB / cell-cycle checkpoint, PI3K / AKT / mTOR.
- PathwayEndometrial cancer (KEGG map)
Shares Letrozole (and other aromatase inhibitors), PIK3CA / PI3K-alpha, Estrogen receptor (ERα), p53 / RB / cell-cycle checkpoint.
- PathwayProstate cancer (KEGG map)
Shares Capivasertib, Enzalutamide, Abiraterone acetate, Androgen receptor.
- PathwayCholine metabolism in cancer
Shares Alpelisib, Capivasertib, PI3K / AKT / mTOR, RAS / RAF / MEK / ERK (MAPK).
- PathwayPancreatic cancer (KEGG map)
Shares JAK2, JAK–STAT signalling, PIK3CA / PI3K-alpha, p53 / RB / cell-cycle checkpoint.
- TrialSOLAR-1
Shares Alpelisib, Fulvestrant, PIK3CA / PI3K-alpha.