title: Ling Zhi-8 mediates p53-dependent growth arrest of lung cancer cells proliferation via the ribosomal protein S7-MDM2-p53 pathway.
abstract: Ling Zhi-8 (LZ-8), an immunomodulatory protein, is derived from and has been cloned from the medicinal mushroom Ganoderma lucidum (Reishi or Ling Zhi); this protein exhibits immunomodulating and antitumor properties. We investigated the effects of recombinant LZ-8 protein (rLZ-8) on the proliferation of A549 human lung cancer cells. Here, we showed that rLZ-8 inhibits cell growth and that this is correlated with increased G(1) arrest. The treatment of A549 cells with rLZ-8 activated p53 and p21 expression, and both the G(1) arrest and the antigrowth effect were found to be p53 dependent. It was further demonstrated that rLZ-8 inhibited tumor growth in mice transplanted with Lewis lung carcinoma cells. Interestingly, rLZ-8 treatment was found to lead to nucleolar stress (or ribosomal stress) as evidenced by inhibition of precursor ribosomal RNA synthesis and reduced polysome formation in A549 cells. These changes resulted in an increasing binding of ribosomal protein S7 to MDM2 and a decreased interaction between MDM2 and p53. Taking these results together, we have identified a novel rLZ-8 antitumor function that positively modulates p53 via ribosomal stress and inhibits lung cancer cell growth in vitro and in vivo. Our current results suggest that rLZ-8 may have potential as a therapeutic intervention for the treatment of cancers that contain wild-type p53 and high expression of MDM2.
authors: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, 155 Li-Nong Street, Shih-Pai Road, Taipei 11221, Taiwan.
authors: Chien-Ting
authors: CT
authors: Wu
authors: Tung-Yi
authors: TY
authors: Lin
authors: Hsien-Yeh
authors: HY
authors: Hsu
authors: Fuu
authors: F
authors: Sheu
authors: Chau-Mei
authors: CM
authors: Ho
authors: Edmund I-T
authors: EI
authors: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects*; D017931:DNA Primers; D005656:Fungal Proteins / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D005656:Fungal Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C037442:ribosomal protein S7; C061148:LZ-8 protein, Ganoderma lucidum; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2