title: E-cadherin increasing multidrug resistance protein 1 via hypoxia-inducible factor-1α contributes to multicellular resistance in colorectal cancer.
abstract: When cancer cells have been cultured as three-dimensional (3D) cultures or in vivo, they decrease sensitivity to anticancer drugs. This is called multicellular resistance, and the mechanism is not fully understood. Here, we report that E-cadherin increasing multidrug resistance protein 1 (MDR1) via hypoxia-inducible factor-1α (HIF-1α) contributes to multicellular resistance in colorectal cancer. The MDR1 protein level was higher in 3D cultures than in monolayer cells. When dispersed cells from 3D cultures were grown as monolayer cells again, the MDR1 protein level decreased to the similar level of cells maintained as monolayer all through. Knockdown of MDR1 significantly decreased multicellular resistance. Knockdown of E-cadherin decreased MDR1 in 3D cultures but did not detectably change MDR1 in monolayer cells. E-cadherin was expressed uniformly in 3D cultures while the MDR1 protein level was higher in the center of 3D cultures than in the peripheral part. Knockdown of E-cadherin decreased E-cadherin uniformly in 3D cultures but mainly decreased MDR1 at the center of 3D cultures. These suggest that knockdown of E-cadherin decreasing MDR1 may be by an indirect mechanism. HIF-1α was remarkably increased in 3D cultures. Knockdown of E-cadherin decreased intercellular junctions, increased intercellular space, and decreased HIF-1α in 3D cultures. Knockdown of HIF-1α decreased MDR1 in 3D cultures. Knockdown of E-cadherin increased β-catenin uniformly in 3D cultures, and knockdown of β-catenin decreased MDR1 what was opposite to knockdown of E-cadherin decreasing MDR1. Our data reveal that knockdown of E-cadherin decreasing MDR1 via HIF-1α is involved in the mechanism of multicellular resistance in colorectal cancer. Though β-catenin is also involved in the mechanism, it does not play a dominant role.
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.|Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Liang
authors.affiliation: Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Fengchao
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. hjmlovelx@hotmail.com.
authors.forename: Jianming
authors.initials: J
authors.lastname: He
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D015703:Antigens, CD; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin
keywords: Colorectal cancer; E-cadherin; Hypoxia-inducible factor-1α; Multicellular resistance; Multidrug resistance protein 1; β-catenin