PMID- 31164954
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231011
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 10
IP  - 36
DP  - 2019 May 21
TI  - Inhibition of DUSP6 sensitizes ovarian cancer cells to chemotherapeutic agents 
      via regulation of ERK signaling response genes.
PG  - 3315-3327
AB  - Dual specificity phosphatase 6 (DUSP6) is a protein phosphatase that deactivates 
      extracellular-signal-regulated kinase (ERK). Since the ovarian cancer biomarker 
      human epididymis protein 4 (HE4) interacts with the ERK pathway, we sought to 
      determine the relationship between DUSP6 and HE4 and elucidate DUSP6's role in 
      epithelial ovarian cancer (EOC). Viability assays revealed a significant decrease 
      in cell viability with pharmacological inhibition of DUSP6 using (E/Z)-BCI 
      hydrochloride in ovarian cancer cells treated with carboplatin or paclitaxel, 
      compared to treatment with either agent alone. Quantitative PCR was used to 
      evaluate levels of ERK pathway response genes to BCI in combination with 
      recombinant HE4 (rHE4), carboplatin, and paclitaxel. Expression of EGR1, a 
      promoter of apoptosis, was higher in cells co-treated with BCI and paclitaxel or 
      carboplatin than in cells treated with chemotherapeutic agents alone, while 
      expression of the proto-oncogene c-JUN was decreased with co-treatment. The 
      effect of BCI on the expression of these two genes opposed that of rHE4. Pathway 
      focused quantitative PCR also revealed suppression of ERBB3 in cells co-treated 
      with BCI plus carboplatin or paclitaxel. Finally, expression levels of DUSP6 in 
      EOC tissue were evaluated by immunohistochemistry, revealing significantly 
      increased levels of DUSP6 in serous EOC tissue compared to adjacent normal 
      tissue. A positive correlation between HE4 and DUSP6 levels was determined by 
      Spearman Rank correlation. In conclusion, DUSP6 inhibition sensitizes ovarian 
      cancer cells to chemotherapeutic agents and alters gene expression of ERK 
      response genes, suggesting that DUSP6 could plausibly function as a novel 
      therapeutic target to reduce chemoresistance in EOC.
FAU - James, Nicole E
AU  - James NE
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
AD  - Department of Pharmacy, University of Rhode Island, Kingston, RI, USA.
FAU - Beffa, Lindsey
AU  - Beffa L
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
FAU - Oliver, Matthew T
AU  - Oliver MT
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
FAU - Borgstadt, Ashley D
AU  - Borgstadt AD
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
FAU - Emerson, Jenna B
AU  - Emerson JB
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
FAU - Chichester, Clinton O
AU  - Chichester CO
AD  - Department of Pharmacy, University of Rhode Island, Kingston, RI, USA.
FAU - Yano, Naohiro
AU  - Yano N
AD  - Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
FAU - Freiman, Richard N
AU  - Freiman RN
AD  - Department of Molecular and Cell Biology and Biochemistry, Brown University, 
      Providence, RI, USA.
FAU - DiSilvestro, Paul A
AU  - DiSilvestro PA
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
FAU - Ribeiro, Jennifer R
AU  - Ribeiro JR
AD  - Women and Infants Hospital, Department of Obstetrics and Gynecology, Program in 
      Women's Oncology, Providence, RI, USA.
LA  - eng
GR  - P30 GM114750/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20190521
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
CIN - Ann Transl Med. 2019 Dec;7(Suppl 8):S373. PMID: 32016091
PMC - PMC6534361
OTO - NOTNLM
OT  - DUSP6
OT  - ERK signaling
OT  - HE4
OT  - chemoresistance
OT  - ovarian cancer
COIS- CONFLICTS OF INTEREST The authors declare no commercial or financial conflicts of 
      interest.
EDAT- 2019/06/06 06:00
MHDA- 2019/06/06 06:01
PMCR- 2019/05/21
CRDT- 2019/06/06 06:00
PHST- 2018/11/07 00:00 [received]
PHST- 2019/04/14 00:00 [accepted]
PHST- 2019/06/06 06:00 [entrez]
PHST- 2019/06/06 06:00 [pubmed]
PHST- 2019/06/06 06:01 [medline]
PHST- 2019/05/21 00:00 [pmc-release]
PST - epublish
SO  - Oncotarget. 2019 May 21;10(36):3315-3327. eCollection 2019 May 21.