Cancer-Preventive Peptide Lunasin from Solanum nigrum L. Inhibits Acetylation of Core Histones H3 and H4 and Phosphorylation of Retinoblastoma Protein (Rb)

Abstract

Lunasin, a unique 43 amino acid, 4.8 kDa cancer-chemopreventive peptide initially reported in soybean and now found in barley and wheat, has been shown to be cancer-chemopreventive in mammalian cells and in a skin cancer mouse model against oncogenes and chemical carcinogens. To identify bioactive components in traditional herbal medicines and in search for new sources of lunasin, we report here the properties of lunasin from Solanum nigrum L. (SNL), a plant indigenous to northeast Asia. Lunasin was screened in the crude extracts of five varieties of the medicinal plants of Solanaceae origin and seven other major herbal plants. An in vitro digestion stability assay for measuring bioavailability was carried out on SNL crude protein and autoclaved SNL using pepsin and pancreatin. A nonradioactive histone acetyltransferase (HAT) assay and HAT activity colorimetric assay were used to measure the inhibition of core histone acetylation. The inhibitory effect of lunasin on the phosphorylation of retinoblastoma protein (Rb) was determined by immunoblotting against phospho-Rb. Lunasin isolated from autoclaved SNL inhibited core histone H3 and H4 acetylation, the activities of the HATs, and the phosphorylation of the Rb protein. Lunasin in the crude protein and in the autoclaved crude protein was very stable to pepsin and pancreatin in vitro digestion, while the synthetic pure lunasin was digested at 2 min after the reaction. We conclude that lunasin is a bioactive and bioavailable component in SNL and that consumption of SNL may play an important role in cancer prevention.

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

“…However, natural agents have not been popularly accepted, primarily due to their poorly defined molecular mechanisms. One such little investigated agent is degalactotigonin (DGT), which is isolated from Solanum nigrum L. The extractions of Solanum nigrum L have anticancer properties in breast cancer, colon cancer, and prostate cancer while leaving normal cells unharmed (8)(9)(10)(11). Thus far, one study has shown growth-inhibitory effects of DGT on a cervical cell line (HeLa) and contraceptive potential but provided no detailed insights into the underlying molecular mechanisms (12).…”

Lunasin: A promising polypeptide for the prevention and treatment of cancer

“…Therefore, the decreased activity of histone acetyltransferases (HATs), including lysine acetyltransferase 2A/2B and p300, is consistent with the decreased incidence of cancer, including colorectal and breast cancer (47)(48)(49). In previous studies, lunasin was demonstrated to competitively inhibit HATs, thereby inhibiting acetylation and regulating the cell cycle (24,32). The underlying molecular mechanisms of the binding of lunasin to histones remain unclear; however, they may be associated with the helical structure formed by the amino acid residues at positions 23-31, and the specific spatial structure or orientation of lunasin (42).…”

“…Following acetylation of HATs, lunasin and HATs competitively deacetylate histones to terminate transcription, thus leading to apoptosis. Therefore, lunasin is involved in the destruction of acetylation-deacetylation kinetics of histones (32). Deacetylated histones are absent from wild-type cells, so lunasin was not able to disrupt the proliferation or cause the apoptosis of wild-type cells.…”

“…Following oral administration of lunasin, it is absorbed into the bloodstream and reaches target tissues or organs in an active and stable state (31). Animal studies using rats fed on a soybean diet rich in lunasin demonstrated that the marked stability of lunasin enables it to reach target tissues and organs following administration, thus serving an important role in the prevention of cancer (24,32). The bioactivity of lunasin has been investigated in humans, and results have demonstrated that 4.5% lunasin at full activity is able to enter the plasma of healthy volunteers in 30 min (33).…”

“…Deacetylated histones are absent from wild-type cells, so lunasin was not able to disrupt the proliferation or cause the apoptosis of wild-type cells. While monitoring the cell cycle process in the presence of lunasin, lunasin was able to be activated to selectively kill tumor cells following the transformation of the cells from wild-type cells to tumor cells, and it was demonstrated that lunasin exhibits a limited number of side effects compared with other drugs (32,53).…”