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.
Highlights
Shikonin is an active component isolated from lithospermum erythrorhizon, a traditional oriental medicinal herb, which has been used to treat HIV-1 infection [1]
To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor Activating transcription factor 2 (ATF2) and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin
At the end of the skin carcinogenesis study, animals’ bodyweights were first measured and the data were presented in the following order: DMSO, SKN, DMBA/TPA, and SKN+DMBA/ TPA: 22.1±2.0g, 22.1±1.9g, 22.0±1.4g, and 21.9±1.4g
Summary
Shikonin is an active component isolated from lithospermum erythrorhizon, a traditional oriental medicinal herb, which has been used to treat HIV-1 infection [1]. Shikonin’s anti-tumor activity has been studied since the 1990s. Shikonin and its derivatives have been shown to induce cell death in a variety of human cancer cells [2,3,4,5,6,7,8,9]. Shikonin and its derivatives show anti-angiogenesis [10,11], anti-inflammation [12], and anti-glycolysis activities [13,14]. The chemopreventive activity of shikonin has been suggested in a rat intestinal.
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