title: Natural pesticide dihydrorotenone arrests human plasma cancer cells at the G0/G1 phase of the cell cycle.
abstract: Dihydrorotenone (DHR) is a natural pesticide used for farming including organic produces. We recently found that DHR induces human plasma cell apoptosis by provoking endoplasmic reticulum stress. In the present study, we found that DHR arrested human plasma cancer cells at the G0/G1 phase of the cell cycle. Mechanistical studies demonstrated that cell cycle arrest was associated with downregulated cell cycle promotors including cyclin D2, cyclin D3, cyclin-dependent kinases (CDK4, CKD6), and phosphorylated-Rb. DHR inhibited cyclin D2 transactivation, thus inhibiting its mRNA expression. In addition, DHR upregulated the cell cycle repressors p21 and p53. DHR also increased the phosphorylation level of p53, suggesting the upregulated transactivation function of p53, which was confirmed by the induction of p21, a substrate of activated p53. Moreover, DHR downregulated AKT and ERK phosphorylation, an incentive of cell cycle progression. Therefore, these results collectively demonstrated that DHR disrupts the cell cycle progress, which suggests that DHR is toxic to human plasma cells. Caution is thus suggested when handling with this agent.
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, People's Republic of China; Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Jieyu
authors.initials: J
authors.lastname: Zhang
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Guodong
authors.initials: G
authors.lastname: Chen
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhang
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056742:Cyclin D2 / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity*; D015394:Molecular Structure; D010950:Plasma Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012402:Rotenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D015398:Signal Transduction
chemical_list: D056742:Cyclin D2; D007306:Insecticides; D012402:Rotenone; C044985:1',2'-dihydrorotenone; D018844:Cyclin-Dependent Kinases
keywords: Cell Cycle; Cell Proliferation; Dihydrorotenone; Pesticide; Plasma Cell