Skin cancer is the most common type of human cancer and is associated with excessive exposure to ultraviolet (UV) solar irradiation. Exposure to UV irradiation can activate various oncogenes and inactivate many tumor suppressor genes. The net result is abnormal proliferation of keratinocytes that might harbor DNA damage leading to the onset of skin cancer (1
). Exposure to UVB irradiation has been shown to induce activation, aggregation, and internalization of cell surface receptors for epidermal growth factor (EGF), tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) (2
Manipulation of the cannabinoid receptors has been useful in the management of pain, treatment of osteoporosis, inflammation, and cancer (4
), but the mechanisms of these effects are still not fully understood. Two cannabinoid receptors from mammalian tissues have been cloned and characterized (5
). Cannabinoid receptor 1 (CB1) is highly expressed in the brain, whereas the CB2 receptor is found mainly in the immune system (5
). However, no direct experimental evidence has confirmed that these membrane-bound receptors are required for UV-induced skin carcinogenesis.
CB1 and CB2 are members of a superfamily of seven-transmembrane-spanning (7-TM) receptors, which have a protein structure defined by an array of seven membrane-spanning helices with intervening intracellular loops and a C-terminal domain that can associate with G proteins. A CB1 (7
) and CB2 homology model (8
) was constructed using the published x-ray crystal structure of bovine rhodopsin (9
), a photosensitive G-protein coupled receptor (GPCR) found in the retina. Arrestin-1 (or visual arrestin) and arrestin-4 (or cone arrestin) modulate the action of rhodopsin (10
) and arrestin-2 and arrestin-3 modulate non-retinal GPCRs (12
). Recently, desensitization of the CB1 receptor was reported to be mediated by the interaction of the C-terminal residues (419–439) of CB1 with arrestin-2 (14
), indicating that CB1 and CB2 might act as a photoreceptor in non-retinal tissues. However, a role for CB1 and CB2 in skin cancer has not been reported. The identification of the “UV-receptor” associated with skin cancer is still to be elucidated and the CB1/2 receptors are potential candidates.
The function of CB1 and CB2 in cancer is controversial. The expression levels of both CB1 and CB2 are significantly higher in CA-human papillomavirus-10 cells, which are virally transformed cells derived from human prostate adenocarcinoma, and also in other human prostate cancer cell lines, including LNCaP, DUI45, PC3, and CWR22Rnu1, compared to human prostate epithelial and PZ-HPV-7 cells that are virally transformed cells derived from normal human prostate tissues (15
). Moreover, the CB1 antagonist, Rimonabant or SR141716, inhibited human breast cancer cell proliferation and was more effective in highly invasive metastatic MDA-MB-231 cells than in the less invasive T47D or MCF-7 cells (16
). In leukemic precursor cells, the CB2 receptor is an oncoprotein that blocks neutrophilic differentiation when overexpressed in myeloid precursor cells (17
). However, treatment of LNCaP cells with WIN-55,212-2, a mixed CB1/CB2 agonist, resulted in inhibition of cell growth and induction of apoptosis (15
). Furthermore, cannabinoids have been shown to suppress the growth of several models of tumor xenografts in rats and mice (19
). CB1 and CB2 receptors are expressed in normal skin and skin tumors and local activation of cannabinoid receptors induced the apoptotic death of tumorigenic epidermal cells, suppressed proliferation of melanoma cells and inhibited the growth and angiogenesis of skin tumor xenografts in nude mice (20
). But cannabinoids may inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism (22
). Therefore, although CB1 and CB2 are physiologically linked with cancer, the functional role of these receptors in cancer is not clear.
Here, we used wildtype CB1/2 (CB1/2+/+) and CB1/2 deficient (CB1/2−/−) mice and respective mouse embryonic fibroblasts (MEFs) to elucidate the function of endogenous CB1 and CB2 in UVB-induced inflammation and skin cancer development.