Silibinin modulates UVB-induced apoptosis via mitochondrial proteins, caspases activation, and mitogen-activated protein kinase signaling in human epidermoid carcinoma A431 cells.
Several recent studies by us have shown the strong chemopreventive efficacy of silibinin against both ultraviolet B (UVB) radiation and chemical carcinogen-induced tumorigenesis in mouse skin models. The molecular mechanisms underlying silibinin protective efficacy, however, are not completely known. Here, we examined the effect of silibinin on UVB-caused apoptosis in human epidermoid carcinoma A431 cells. Irradiation of cells with different doses of UVB (5-100 mJ/cm2) and different time periods (0.5-24h) resulted in a dose- and time-dependent increase in apoptosis (P < 0.05-0.001). Silibinin (100-200 microM) pre-treatment, however, resulted in an increase in UVB-induced apoptosis (P < 0.05-0.001); interestingly, its post-treatment caused a decrease in UVB-induced apoptosis (P < 0.05-0.001). A similar pattern in the activation of caspases-9, -3, and -7 was observed with these silibinin treatments. Further, silibinin treatment prior to or immediately after UVB exposure altered Bcl-2, Bax, Bak, and cytochrome c levels in mitochondria and cytosol in favor of or against apoptosis, respectively. Silibinin treatment prior to UVB also increased the activation of mitogen/stress activated protein kinases Erk1/2, JNK, and p38 kinase as compared to its post-treatment. Together, for the first time, our results demonstrate the role of mitochondrial apoptotic machinery and MAPK signaling cascade in silibinin-caused increase as well as protection in UVB-induced apoptosis in A431 cells, and suggest that similar mechanisms might be involved in preventive efficacy of silibinin against UVB-induced skin tumorigenesis.
Mohan
Sarumathi
S
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Dhanalakshmi
Sivanandhan
S
Mallikarjuna
G U
GU
Singh
Rana P
RP
Agarwal
Rajesh
R
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays
D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases