Inhibitory effect of glycolic acid on ultraviolet-induced skin tumorigenesis in SKH-1 hairless mice and its mechanism of action.
Glycolic acid, an alpha-hydroxy acid derived from fruit and milk sugars, has been used commonly as a cosmetic ingredient since it was discovered to have photoprotective and anti-inflammatory effects and antioxidant effects on ultraviolet (UV)B-irradiated skin. Little is known, however, about the functional role of glycolic acid on UV-induced skin tumorigenesis. In the present study, we examined the effect of glycolic acid on UV (UVA + UVB)-induced skin tumorigenesis and assessed several significant contributing factors in SKH-1 hairless mice. Inbred hairless female mice (15 animals/group) were irradiated for 5 d/wk at a total dose of 74.85 J/cm(2) UVA and 2.44 J/cm(2) UVB for 22 wk. Glycolic acid was applied topically twice a week at a dose of 8 mg/cm(2) immediately after UV irradiation. Glycolic acid reduced UV-induced skin tumor development. The protective effect of glycolic acid was a 20% reduction of skin tumor incidence, a 55% reduction of tumor multiplicity (average number of tumors/mouse), and a 47% decrease in the number of large tumors (larger than 2 mm). Glycolic acid also delayed the first appearance of tumor formation by about 3 wk. The inhibitory effect of glycolic acid on UV-induced tumor development was accompanied by decreased expression of the following UV-induced cell-cycle regulatory proteins: proliferating cell nuclear antigen (PCNA), cyclin D1, cyclin E, and the associated subunits cyclin-dependent kinase 2 (cdk2) and cdk4. In addition, the expression of p38 kinase, jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase (MEK) also was lower in UV + glycolic acid-treated skin compared with expression in UV-irradiated skin. Moreover, transcription factors activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) activation was significantly lower in UV + glycolic acid-treated skin compared with activation in UV-irradiated skin. These results show that glycolic acid reduced UV-induced skin tumor development. The decreased expression of the cell-cycle regulatory proteins PCNA, cyclin D1, cyclin E, cdk2, and cdk4 and the signal mediators JNK, p38 kinase, and MEK may play a significant role in the inhibitory effect of glycolic acid on UV-induced skin tumor development. In addition, the inhibition of activation of transcription factors AP-1 and NF-kappaB could contribute significantly to the inhibitory effect of glycolic acid.
Hong
J T
JT
Department of Toxicology, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea.
Kim
E J
EJ
Ahn
K S
KS
Jung
K M
KM
Yun
Y P
YP
Park
Y K
YK
Lee
S H
SH
D000818:Animals; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D006016:Glycolates / Q000494:pharmacology*; D051379:Mice; D008812:Mice, Hairless; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays
D019927:Cyclin E; D006016:Glycolates; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C031149:glycolic acid; D019938:Cyclin D1; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases