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Invalidation of mitophagy by FBP1-mediated repression promotes apoptosis in breast cancer.

Abstract Fructose-1,6-bisphosphatase 1, a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor. However, the functions of fructose-1,6-bisphosphatase 1 in the regulation of mitophagy and apoptosis remain unknown. Here, we investigated the effects of fructose-1,6-bisphosphatase 1 on mitophagy and apoptosis as well as their underlying mechanisms in breast cancer cells. In this work, the messenger RNA and protein expression of various molecules were determined by quantitative realtime polymerase chain reaction and western blot, respectively. Gene-expression correlations were obtained from The Cancer Genome Atlas Breast Cancer database and analyzed using cBioPortal. The levels of cellular reactive oxygen species and apoptotic index were detected by flow cytometry. The mitochondrial membrane potentials were assessed with a JC-1 fluorescent sensor. Subcellular structures were observed under a transmission electron microscope. The intracellular distribution of translocase of outer membrane 20 was detected by immunofluorescence staining. Protein-protein interactions were analyzed by immunoprecipitation. Our results indicated that fructose-1,6-bisphosphatase 1 expression was negatively correlated with autophagy level in breast cancer. Fructose-1,6-bisphosphatase 1 restrained autophagy activity by increasing the level of p62 and decreasing the levels of LC3 and Beclin 1. Additionally, fructose-1,6-bisphosphatase 1 promoted cell apoptosis by upregulating the levels of intracellular ROS and expression of pro-apoptotic proteins such as cleaved PARP, cleaved Caspase 3, and Bax and downregulating the levels of anti-apoptotic proteins such as PARP, Caspase 3, and Bcl-2. Finally, fructose-1,6-bisphosphatase 1 limited the efficient removal of diseased mitochondria and reduced the messenger RNA and protein expressions of HIF-1α, BNIP3L/NIX, and BNIP3. More importantly, fructose-1,6-bisphosphatase 1 facilitated co-action between Bcl-2 and Beclin 1, which may be important in the mechanism of fructose-1,6-bisphosphatase 1-mediated mitophagy inhibition. In summary, loss of mitophagy by fructose-1,6-bisphosphatase 1-mediated repression promotes apoptosis in breast cancer.
PMID
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Authors

Mayor MeshTerms
Keywords

Breast cancer

apoptosis

fructose-1,6-bisphosphatase 1

mitophagy

reactive oxygen species

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28653874
OWN - NLM
STAT- MEDLINE
DA  - 20170627
DCOM- 20170711
LR  - 20170713
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 6
DP  - 2017 Jun
TI  - Invalidation of mitophagy by FBP1-mediated repression promotes apoptosis in
      breast cancer.
PG  - 1010428317708779
LID - 10.1177/1010428317708779 [doi]
AB  - Fructose-1,6-bisphosphatase 1, a rate-limiting enzyme in gluconeogenesis, was
      recently shown to be a tumor suppressor. However, the functions of
      fructose-1,6-bisphosphatase 1 in the regulation of mitophagy and apoptosis remain
      unknown. Here, we investigated the effects of fructose-1,6-bisphosphatase 1 on
      mitophagy and apoptosis as well as their underlying mechanisms in breast cancer
      cells. In this work, the messenger RNA and protein expression of various
      molecules were determined by quantitative realtime polymerase chain reaction and 
      western blot, respectively. Gene-expression correlations were obtained from The
      Cancer Genome Atlas Breast Cancer database and analyzed using cBioPortal. The
      levels of cellular reactive oxygen species and apoptotic index were detected by
      flow cytometry. The mitochondrial membrane potentials were assessed with a JC-1
      fluorescent sensor. Subcellular structures were observed under a transmission
      electron microscope. The intracellular distribution of translocase of outer
      membrane 20 was detected by immunofluorescence staining. Protein-protein
      interactions were analyzed by immunoprecipitation. Our results indicated that
      fructose-1,6-bisphosphatase 1 expression was negatively correlated with autophagy
      level in breast cancer. Fructose-1,6-bisphosphatase 1 restrained autophagy
      activity by increasing the level of p62 and decreasing the levels of LC3 and
      Beclin 1. Additionally, fructose-1,6-bisphosphatase 1 promoted cell apoptosis by 
      upregulating the levels of intracellular ROS and expression of pro-apoptotic
      proteins such as cleaved PARP, cleaved Caspase 3, and Bax and downregulating the 
      levels of anti-apoptotic proteins such as PARP, Caspase 3, and Bcl-2. Finally,
      fructose-1,6-bisphosphatase 1 limited the efficient removal of diseased
      mitochondria and reduced the messenger RNA and protein expressions of HIF-1alpha,
      BNIP3L/NIX, and BNIP3. More importantly, fructose-1,6-bisphosphatase 1
      facilitated co-action between Bcl-2 and Beclin 1, which may be important in the
      mechanism of fructose-1,6-bisphosphatase 1-mediated mitophagy inhibition. In
      summary, loss of mitophagy by fructose-1,6-bisphosphatase 1-mediated repression
      promotes apoptosis in breast cancer.
FAU - Liu, Yifeng
AU  - Liu Y
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Jiang, Yulin
AU  - Jiang Y
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Wang, Nian
AU  - Wang N
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Jin, Qianni
AU  - Jin Q
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Ji, Feihu
AU  - Ji F
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Zhong, Changli
AU  - Zhong C
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Zhang, Zhiqiang
AU  - Zhang Z
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Yang, Junhong
AU  - Yang J
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Ye, Xiangsen
AU  - Ye X
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
FAU - Chen, Tingmei
AU  - Chen T
AD  - Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education,
      Chongqing Medical University, Chongqing, P.R. China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (Beclin-1)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FUBP1 protein, human)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.6.4.- (DNA Helicases)
SB  - IM
MH  - Apoptosis/genetics
MH  - Autophagy/genetics
MH  - Beclin-1/*genetics
MH  - Breast Neoplasms/*genetics/pathology
MH  - DNA Helicases/*genetics
MH  - DNA-Binding Proteins/*genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - MCF-7 Cells
MH  - Mitochondria/genetics
MH  - Mitochondrial Degradation/genetics
MH  - Protein Interaction Maps/genetics
MH  - Proto-Oncogene Proteins c-bcl-2/*genetics
MH  - Reactive Oxygen Species/metabolism
OTO - NOTNLM
OT  - Breast cancer
OT  - apoptosis
OT  - fructose-1,6-bisphosphatase 1
OT  - mitophagy
OT  - reactive oxygen species
EDAT- 2017/06/28 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/28 06:00
AID - 10.1177/1010428317708779 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jun;39(6):1010428317708779. doi: 10.1177/1010428317708779.