The Chinese herb isolate yuanhuacine (YHL-14) induces G2/M arrest in human cancer cells by up-regulating p21 protein expression through an p53 protein-independent cascade.
Yuanhuacine (YHL-14), the major component of daphnane diterpene ester isolated from the flower buds of Daphne genkwa, has been reported to have activity against cell proliferation in various cancer cell lines. Nevertheless, the potential mechanism has not been explored yet. Here we demonstrate that YHL-14 inhibits bladder and colon cancer cell growth through up-regulation of p21 expression in an Sp1-dependent manner. We found that YHL-14 treatment resulted in up-regulation of p21 expression and a significant G2/M phase arrest in T24T and HCT116 cells without affecting p53 protein expression and activation. Further studies indicate that p21 induction by YHL-14 occurs at the transcriptional level via up-regulation of Sp1 protein expression. Moreover, our results show that p38 is essential for YHL-14-mediated Sp1 protein stabilization, G2/M growth arrest induction, and anchorage-independent growth inhibition of cancer cells. Taken together, our studies demonstrate a novel mechanism of YHL-14 against cancer cell growth in bladder and colon cancer cell lines, which provides valuable information for the design and synthesis of other new conformation-constrained derivatives on the basis of the structure of YHL-14 for cancer therapy.
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987; Key Laboratory of Structure-based Drug Design and Discovery, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Ruowen
R
Zhang
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Yulei
Y
Wang
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Jingxia
J
Li
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987.
Honglei
H
Jin
Key Laboratory of Structure-based Drug Design and Discovery, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: songsj99@gmail.com.
Shaojiang
S
Song
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987. Electronic address: chuanshu.huang@nyumc.org.
Chuanshu
C
Huang
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D032364:Daphne / Q000737:chemistry*; D004224:Diterpenes / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D016159:Tumor Suppressor Protein p53; C029912:Yuanhuacin
Anticancer Drug; Cell Growth; MAPK; Protein Stability; Sp1; Yuanhuacine; p21; p38