title: Depletion of 4E-BP1 and regulation of autophagy lead to YXM110-induced anticancer effects.
abstract: Natural products have always been a profuse database for developing new chemotherapeutics. YXM110 is a newly synthesized phenanthroquinolizidines that exhibits excellent anticancer activity in numerous cancer cells. In this study, we examined the anticancer mechanisms of YXM110 both in vitro and in vivo. Protein level of 4E-binding protein 1, which is crucial in cap-independent translation, was decreased significantly after YXM110 treatment via c-Jun N-terminal kinases-mediated proteasomal degradation. Moreover, the effects of YXM110 were associated with several characteristics of autophagy, including accumulation of autophagic vacuoles, elevation of Atg12-Atg5 and light chain 3 (LC3)-II, and levels of GFP-LC3 puncta. The results suggested that depletion of Mcl-1 contributes to YXM110-triggered autophagy, whereas downregulation of lysosomal-related genes could cause autophagy impairment. Furthermore, YXM110-induced cell death was prevented by autophagy inhibitor 3-methyladenine and Atg5 silencing, indicating that YXM110-mediated autophagy impairment leads to cancer cell death. These data reveal key mechanisms that support the further development of YXM110 as a promising anticancer agent.
authors: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Chin-Yu
authors: CY
authors: Lai
authors: Shiow-Lin
authors: SL
authors: Pan
authors: Xiao-Ming
authors: XM
authors: Yang
authors: Li-Hsun
authors: LH
authors: Chang
authors: Ya-Ling
authors: YL
authors: Chang
authors: Pan-Chyr
authors: PC
authors: Yang
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Che-Ming
authors: CM
authors: Teng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics*; D000470:Alkaloids / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010616:Phenanthrenes / Q000008:administration & dosage*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D054837:Quinolizidines / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000470:Alkaloids; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D008869:Microtubule-Associated Proteins; D010616:Phenanthrenes; D010750:Phosphoproteins; D054837:Quinolizidines; C000609610:YXM110; C007160:cryptopleurine; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases