title: The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation.
abstract: Metabolic stress induces autophagy as an alternative source of energy and metabolites. Insufficient autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. Here, we performed a functional screen in search of novel autophagy regulators from natural products. We showed that oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes and impaired degradation of SQSTM1/p62. Costaining of GFP-LC3B with LysoTracker Red or LAMP1 antibody demonstrates that autophagosome-lysosome fusion is blocked by OC treatment. Furthermore, OC inhibits lysosomal proteolytic activity by altering lysosomal acidification and downregulating the expression of lysosomal cathepsins. Importantly, OC can eliminate the tolerance of cancer cells to nutrient starvation. Starvation dramatically increases the susceptibility of cancer cells to OC-induced CASP3-dependent apoptosis in vitro. Subsequent studies in xenograft mouse model showed that OC has anticancer potency as revealed by increased staining of cleaved CASP3, LC3 puncta, and SQSTM1, as well as reduced expression of lysosomal cathepsins. Combined treatment with OC and caloric restriction potentiates anticancer efficacy of OC in vivo. Collectively, these data demonstrated that OC is a novel autophagic flux inhibitor and might be useful in anticancer therapy.
authors.affiliation: School of Pharmacy; Shanghai University of Traditional Chinese Medicine; Shanghai, China.
authors.forename: Yuanzhi
authors.initials: Y
authors.lastname: Lao
authors.affiliation: Key Lab in Healthy Science and Technology; Division of Life Science; Graduate School at Shenzhen; Tsinghua University; Shenzhen,China; School of Life Sciences; Tsinghua University; Beijing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wan
authors.affiliation: School of Pharmacy; Shanghai University of Traditional Chinese Medicine; Shanghai, China.
authors.forename: Zhenyan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmacy; Shanghai University of Traditional Chinese Medicine; Shanghai, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology; Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine; Nanning, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ruan
authors.affiliation: Key Lab in Healthy Science and Technology; Division of Life Science; Graduate School at Shenzhen; Tsinghua University; Shenzhen,China; School of Life Sciences; Tsinghua University; Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: School of Pharmacy; Shanghai University of Traditional Chinese Medicine; Shanghai, China; Department of Discovery Technologies; Roche R&D Center (China) Ltd; Shanghai, China.
authors.forename: Danqing
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Lab in Healthy Science and Technology; Division of Life Science; Graduate School at Shenzhen; Tsinghua University; Shenzhen,China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Xie
authors.affiliation: Key Lab in Healthy Science and Technology; Division of Life Science; Graduate School at Shenzhen; Tsinghua University; Shenzhen,China.
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy; Shanghai University of Traditional Chinese Medicine; Shanghai, China.
authors.forename: Hongxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Lab in Healthy Science and Technology; Division of Life Science; Graduate School at Shenzhen; Tsinghua University; Shenzhen,China.
authors.forename: Naihan
authors.initials: N
authors.lastname: Xu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D005502:Food; D005508:Food Deprivation / Q000502:physiology*; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D013729:Terpenes / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D013729:Terpenes; C575447:oblongifolin C
keywords: apoptosis; autophagy; cancer; lysosome; natural product; oblongifolin C