title: Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.
abstract: The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Chunjing
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Teena
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.affiliation: Feist-Weiller Cancer Center, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Runhua
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Toxicology & Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, Louisiana, United States of America.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D051698:Activating Transcription Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009285:Naphthoquinones / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011725:Pyridines; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000097810:Thyroid Hormone-Binding Proteins; D000099169:Fos-Related Antigen 1
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D051698:Activating Transcription Factor 2; D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D002352:Carrier Proteins; D051358:Cyclin-Dependent Kinase 4; D008565:Membrane Proteins; D009285:Naphthoquinones; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; D000099169:Fos-Related Antigen 1; C497106:Atf2 protein, mouse; C431843:tris(2-pyridylmethyl)amine; C016101:shikonin; C495902:Cdk4 protein, mouse