title: Suppression of HSP27 increases the anti‑tumor effects of quercetin in human leukemia U937 cells.
abstract: Quercetin, a natural flavonoid, inhibits the growth of leukemia cells and induces apoptosis. Heat shock protein 27 (HSP27) has been reported to promote the development of leukemia by protecting tumor cells from apoptosis through various mechanisms. The present study investigated the effects of small hairpin (sh)RNA-mediated HSP27 knockdown on the anti‑cancer effects of quercetin in U937 human leukemia cells. Cells were transfected with recombinant lentiviral vector pCMV‑G‑NR‑U6‑shHSP27 (shHSP27), which expressed shRNA specifically targeting the HSP27 gene, alone or in combination with quercetin. The results showed that shHSP27 and quercetin synergistically inhibited U937 cell proliferation and induced apoptosis by decreasing the Bcl2-to-Bax ratio. Furthermore, this combined treatment significantly suppressed the infiltration of tumor cells and the expression of angiogenesis‑associated proteins HIF1α and VEGF. Compared with shHSP27 or quercetin alone, shHSP27 plus quercetin markedly decreased the protein expression of cyclinD1 and thus blocked the cell cycle at G1 phase. The Notch/AKT/mTOR signaling pathway is important in tumor aggressiveness; quercetin plus shHSP27 significantly decreased Notch 1 expression and the phosphorylation levels of the downstream signaling proteins AKT and mTOR. The inhibitory effects of quercetin plus shHSP27 on this pathway may thus have been responsible for the cell cycle arrest, inhibition of proliferations and infiltration as well as enhancement of apoptosis. Therefore, these findings collectively suggested that suppression of HSP27 expression amplified the anti‑cancer effects of quercetin in U937 human leukemia cells, and that quercetin in combination with shHSP27 represents a promising therapeutic strategy for human leukemia.
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Xiu-Shuai
authors.initials: XS
authors.lastname: Dong
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Gao
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Yong-Fang
authors.initials: YF
authors.lastname: Jiang
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Jin
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Chang
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Department of Hematology, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D055785:Gene Knockdown Techniques; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D018832:Molecular Chaperones; D011794:Quercetin / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D011794:Quercetin