PMID- 24901645
OWN - NLM
STAT- MEDLINE
DCOM- 20150805
LR  - 20220318
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 6
DP  - 2014
TI  - HIF-1alpha inhibition reverses multidrug resistance in colon cancer cells via 
      downregulation of MDR1/P-glycoprotein.
PG  - e98882
LID - 10.1371/journal.pone.0098882 [doi]
LID - e98882
AB  - BACKGROUND: Multidrug resistance (MDR) is one of the major reasons 
      chemotherapy-based treatments fail. Hypoxia is generally associated with tumor 
      chemoresistance. However, the correlation between the heterodimeric 
      hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance (MDR1) 
      gene/transporter P-glycoprotein (P-gp) remains unclear. This study aims to 
      explore the molecular mechanisms of reversing colon cancer MDR by focusing on the 
      target gene HIF-1alpha. METHODS: A chemotherapeutic sensitivity assay was used to 
      observe the efficiency of MDR reversal in LoVo multicellular spheroids (MCS). The 
      apoptotic level induced by different drugs was examined by flow cytometry (FCM). 
      Binding of HIF-1alpha to the MDR1 gene promoter was evaluated by Chromatin 
      immunoprecipitation (ChIP). The relationship between HIF-1alpha/P-gp expression and 
      sensitivity to chemotherapy was analyzed. RESULTS: The sensitivity of LoVo MCS to 
      all four chemotherapy drugs was decreased to varying degrees under hypoxic 
      conditions. After silencing the HIF-1alpha gene, the sensitivities of LoVo MCS to all 
      four chemotherapy drugs were restored. The apoptotic levels that all the drugs 
      induced were all decreased to various extents in the hypoxic group. After 
      silencing HIF-1alpha, the apoptosis level induced by all four chemotherapy drugs 
      increased. The expression of HIF-1alpha and P-gp was significantly enhanced in LoVo 
      MCS after treatment with hypoxia. Inhibiting HIF-1alpha significantly decreased the 
      expression of MDR1/P-gp mRNA or protein in both the LoVo monolayers and LoVo MCS. 
      The ChIP assay showed that HIF-1alpha was bound to the MDR1 gene promoter. Advanced 
      colon carcinoma patients with expression of both HIF-1alpha and P-gp were more 
      resistant to chemotherapy than that with non expression. CONCLUSIONS: HIF-1alpha 
      inhibition reverses multidrug resistance in colon cancer cells via downregulation 
      of MDR1/P-gp. The expression of HIF-1alpha and MDR1/P-gp can be used as a predictive 
      marker for chemotherapy resistance in colon cancer.
FAU - Chen, Jianfang
AU  - Chen J
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
FAU - Ding, Zhenyu
AU  - Ding Z
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China; Department of Oncology, General 
      Hospital of Shenyang Military Region, Shenyang, Liaoning, China.
FAU - Peng, Yonghai
AU  - Peng Y
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
FAU - Pan, Feng
AU  - Pan F
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
FAU - Li, Jianjun
AU  - Li J
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
FAU - Zou, Lan
AU  - Zou L
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
FAU - Zhang, Yanling
AU  - Zhang Y
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
FAU - Liang, Houjie
AU  - Liang H
AD  - Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third 
      Military Medical University, Chongqing, China.
LA  - eng
PT  - Journal Article
DEP - 20140605
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B/*genetics
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/drug effects/genetics
MH  - Cell Line, Tumor
MH  - Colonic Neoplasms/*genetics/*metabolism
MH  - Drug Resistance, Neoplasm/*genetics
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Hypoxia/genetics/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - RNA Interference
MH  - RNA, Messenger/genetics
MH  - RNA, Small Interfering/genetics
MH  - Transcription, Genetic
PMC - PMC4047061
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/06/06 06:00
MHDA- 2015/08/06 06:00
PMCR- 2014/06/05
CRDT- 2014/06/06 06:00
PHST- 2013/12/07 00:00 [received]
PHST- 2014/05/08 00:00 [accepted]
PHST- 2014/06/06 06:00 [entrez]
PHST- 2014/06/06 06:00 [pubmed]
PHST- 2015/08/06 06:00 [medline]
PHST- 2014/06/05 00:00 [pmc-release]
AID - PONE-D-13-49685 [pii]
AID - 10.1371/journal.pone.0098882 [doi]
PST - epublish
SO  - PLoS One. 2014 Jun 5;9(6):e98882. doi: 10.1371/journal.pone.0098882. eCollection 
      2014.