title: Induction of Cbl-dependent epidermal growth factor receptor degradation in Ling Zhi-8 suppressed lung cancer.
abstract: Activating mutation of epidermal growth factor receptor (EGFR) is correlated with malignant lung tumor. In our study, we demonstrated that recombinant LZ-8 (rLZ-8), a medicinal mushroom Ganoderma lucidum protein, induced cell cycle arrest and apoptosis by downregulating the expression of wild-type and mutated EGFR and inhibiting EGFR downstream effectors, AKT and ERK1/2 in lung cancer cells. We showed that rLZ-8 effectively inhibited lung cancer progression and suppressed EGFR expression of lung tumor lesions in mouse model. Functional studies revealed that rLZ-8 reduced the amount of EGFR in cell membranes by altering EGFR localization to enhance the EGF-induced degradation of EGFR. Mechanistically, we demonstrated that rLZ-8 bound to EGFR to induce EGFR autophosphorylation at tyrosine1045 and trigger ubiquitination by inducing the formation of EGFR/Cbl complexes, resulting in the degradation of EGFR; however, Cbl-shRNA abolished rLZ-8-induced EGFR degradation. We provide the first evidence showing that rLZ-8 inhibits growth and induces apoptosis of lung cancer cells by promoting EGFR degradation. The current findings therefore suggest a novel anti-cancer function of rLZ-8 that targeting EGFR overexpression or mutation as well as EGFR-dependent processes in cancer cells.
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tung-Yi
authors.identifier: 0000-0003-1199-1121
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.|The Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsien-Yeh
authors.identifier: 0000-0002-3414-1448
authors.initials: HY
authors.lastname: Hsu
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wei-Hsuan
authors.initials: WH
authors.lastname: Sun
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Wu
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Tsao
mesh_terms: D000072283:A549 Cells; D000363:Agaricales / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D005656:Fungal Proteins / Q000191:economics / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D050722:Oncogene Protein v-cbl / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology*; D020940:Reishi / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D050722:Oncogene Protein v-cbl; D011994:Recombinant Proteins; C061148:LZ-8 protein, Ganoderma lucidum; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Cbl; EGFR; Ling Zhi-8; Lung cancer; Ubiquitin-proteasome pathway