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Inhibitory effect of Par-4 combined with cisplatin on human Wilms' tumor cells.

Abstract Wilms' tumor is associated with a high treatment success rate, but there is still a risk of recurrence. Cisplatin, which is one of the chemotherapeutic agents used for its treatment, is associated with a very high rate of resistance. Par-4 (prostate apoptosis response 4) is a tumor suppressor, which is capable of sensitizing tumor cells to chemotherapy. Therefore, the aim of this study was to determine whether combined treatment with Par-4 and cisplatin is effective for inhibiting growth of Wilms' tumor. Wilms' tumor and control cell samples were collected and analyzed by immunofluorescence assay and immunohistochemistry. Total proteins extracted from cultured cells were analyzed using western blotting and flow cytometry. In addition, a mouse xenograft model was established. We discovered significantly low expression of Par-4 in the tumor tissue, which was positively correlated with high expression of GRP78 (glucose-regulated protein 78). In addition, we found that ectopic Par-4 co-localized with cell surface GRP78 and induced high expression of the endoplasmic reticulum proteins ATF4 and BAX, which activated the endoplasmic reticulum apoptosis pathway. Moreover, treatment with ectopic Par-4 and cisplatin suppressed xenograft growth in nude mice. In conclusion, our results showed that Par-4 overexpression and cisplatin had a synergistic effect on SK-NEP-1 cells, as a result of which cell growth was inhibited and cellular apoptosis was induced. Thus, in vitro and in vivo upregulation of Par-4 expression is indispensable for the trafficking of GRP78 to the cell membrane and subsequent apoptosis of cancer cells.
PMID
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Authors

Mayor MeshTerms
Keywords

Nephroblastoma

apoptosis

cisplatin

glucose-regulated protein 78

prostate apoptosis response 4

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




PMID- 28720068
OWN - NLM
STAT- In-Process
DA  - 20170719
LR  - 20170719
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 7
DP  - 2017 Jul
TI  - Inhibitory effect of Par-4 combined with cisplatin on human Wilms' tumor cells.
PG  - 1010428317716689
LID - 10.1177/1010428317716689 [doi]
AB  - Wilms' tumor is associated with a high treatment success rate, but there is still
      a risk of recurrence. Cisplatin, which is one of the chemotherapeutic agents used
      for its treatment, is associated with a very high rate of resistance. Par-4
      (prostate apoptosis response 4) is a tumor suppressor, which is capable of
      sensitizing tumor cells to chemotherapy. Therefore, the aim of this study was to 
      determine whether combined treatment with Par-4 and cisplatin is effective for
      inhibiting growth of Wilms' tumor. Wilms' tumor and control cell samples were
      collected and analyzed by immunofluorescence assay and immunohistochemistry.
      Total proteins extracted from cultured cells were analyzed using western blotting
      and flow cytometry. In addition, a mouse xenograft model was established. We
      discovered significantly low expression of Par-4 in the tumor tissue, which was
      positively correlated with high expression of GRP78 (glucose-regulated protein
      78). In addition, we found that ectopic Par-4 co-localized with cell surface
      GRP78 and induced high expression of the endoplasmic reticulum proteins ATF4 and 
      BAX, which activated the endoplasmic reticulum apoptosis pathway. Moreover,
      treatment with ectopic Par-4 and cisplatin suppressed xenograft growth in nude
      mice. In conclusion, our results showed that Par-4 overexpression and cisplatin
      had a synergistic effect on SK-NEP-1 cells, as a result of which cell growth was 
      inhibited and cellular apoptosis was induced. Thus, in vitro and in vivo
      upregulation of Par-4 expression is indispensable for the trafficking of GRP78 to
      the cell membrane and subsequent apoptosis of cancer cells.
FAU - Wang, Jun
AU  - Wang J
AD  - 1 Department of Urology, Children's Hospital of Nanjing Medical University,
      Nanjing, China.
FAU - Li, Yunjie
AU  - Li Y
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Ma, Fangfang
AU  - Ma F
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Zhou, Huifeng
AU  - Zhou H
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Ding, Rong
AU  - Ding R
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Lu, Binbin
AU  - Lu B
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Zou, Li
AU  - Zou L
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Li, Junxia
AU  - Li J
AD  - 2 Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical
      University, Nanjing, China.
FAU - Lu, Rugang
AU  - Lu R
AD  - 1 Department of Urology, Children's Hospital of Nanjing Medical University,
      Nanjing, 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
OTO - NOTNLM
OT  - Nephroblastoma
OT  - apoptosis
OT  - cisplatin
OT  - glucose-regulated protein 78
OT  - prostate apoptosis response 4
EDAT- 2017/07/20 06:00
MHDA- 2017/07/20 06:00
CRDT- 2017/07/20 06:00
AID - 10.1177/1010428317716689 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jul;39(7):1010428317716689. doi: 10.1177/1010428317716689.