TY - JOUR
T1 - JNK inhibition blocks piperlongumine-induced cell death and transcriptional activation of heme oxygenase-1 in pancreatic cancer cells
AU - Mohammad, Jiyan
AU - Singh, Rahul R.
AU - Riggle, Cody
AU - Haugrud, Brandon
AU - Abdalla, Maher Y.
AU - Reindl, Katie M.
N1 - Funding Information:
Funding NIH Grant number 1P20GM109024 (to KMR). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Funding Information:
and Megan Orr for their technical support and assistance. We would like to acknowledge the use of the Biostatistics Core Facility for statistical analysis in this manuscript. This study is funded by National Institute of General Medical Sciences of the National Institutes of Health, Award Number 1P20GM109024.
Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/10/15
Y1 - 2019/10/15
N2 - Piperlongumine (PL) is an alkaloid that inhibits glutathione S-transferase pi 1 (GSTP1) activity, resulting in elevated reactive oxygen species (ROS) levels and cancer-selective cell death. We aimed to identify stress-associated molecular responses to PL treatment in pancreatic ductal adenocarcinoma (PDAC) cells. GSTP1 directly interacts with JNK, which is activated by oxidative stress and can lead to decreased cancer cell proliferation and cell death. Therefore, we hypothesized that JNK pathways are activated in response to PL treatment. Our results show PL causes dissociation of GSTP1 from JNK; robust JNK, c-Jun, and early ERK activation followed by suppression; increased expression of cleaved caspase-3 and cleaved PARP; and nuclear translocation of Nrf2 and c-Myc in PDAC cells. Gene expression analysis revealed PL caused a > 20-fold induction of heme oxygenase-1 (HO-1), which we hypothesized was a survival mechanism for PDAC cells under enhanced oxidative stress. HO-1 knockout resulted in enhanced PL-induced PDAC cell death under hypoxic conditions. Similarly, high concentrations of the HO-1 inhibitor, ZnPP (10 µM), sensitized PDAC cells to PL; however, lower concentrations ZnPP (10 nM) and high or low concentrations of SnPP both protected PDAC cells from PL-induced cell death. Interestingly, the JNK inhibitor significantly blocked PL-induced PDAC cell death, Nrf-2 nuclear translocation, and HMOX-1 mRNA expression. Collectively, the results demonstrate JNK signaling contributes to PL-induced PDAC cell death, and at the same time, activates Nrf-2 transcription of HMOX-1 as a compensatory survival mechanism. These results suggest that elevating oxidative stress (using PL) while at the same time impairing antioxidant capacity (inhibiting HO-1) may be an effective therapeutic approach for PDAC.
AB - Piperlongumine (PL) is an alkaloid that inhibits glutathione S-transferase pi 1 (GSTP1) activity, resulting in elevated reactive oxygen species (ROS) levels and cancer-selective cell death. We aimed to identify stress-associated molecular responses to PL treatment in pancreatic ductal adenocarcinoma (PDAC) cells. GSTP1 directly interacts with JNK, which is activated by oxidative stress and can lead to decreased cancer cell proliferation and cell death. Therefore, we hypothesized that JNK pathways are activated in response to PL treatment. Our results show PL causes dissociation of GSTP1 from JNK; robust JNK, c-Jun, and early ERK activation followed by suppression; increased expression of cleaved caspase-3 and cleaved PARP; and nuclear translocation of Nrf2 and c-Myc in PDAC cells. Gene expression analysis revealed PL caused a > 20-fold induction of heme oxygenase-1 (HO-1), which we hypothesized was a survival mechanism for PDAC cells under enhanced oxidative stress. HO-1 knockout resulted in enhanced PL-induced PDAC cell death under hypoxic conditions. Similarly, high concentrations of the HO-1 inhibitor, ZnPP (10 µM), sensitized PDAC cells to PL; however, lower concentrations ZnPP (10 nM) and high or low concentrations of SnPP both protected PDAC cells from PL-induced cell death. Interestingly, the JNK inhibitor significantly blocked PL-induced PDAC cell death, Nrf-2 nuclear translocation, and HMOX-1 mRNA expression. Collectively, the results demonstrate JNK signaling contributes to PL-induced PDAC cell death, and at the same time, activates Nrf-2 transcription of HMOX-1 as a compensatory survival mechanism. These results suggest that elevating oxidative stress (using PL) while at the same time impairing antioxidant capacity (inhibiting HO-1) may be an effective therapeutic approach for PDAC.
KW - Apoptosis
KW - GSTP1 inhibitor
KW - Nrf2
KW - Oxidative stress
KW - SnPP
KW - ZnPP
UR - http://www.scopus.com/inward/record.url?scp=85068123064&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068123064&partnerID=8YFLogxK
U2 - 10.1007/s10495-019-01553-9
DO - 10.1007/s10495-019-01553-9
M3 - Article
C2 - 31243599
AN - SCOPUS:85068123064
SN - 1360-8185
VL - 24
SP - 730
EP - 744
JO - Apoptosis
JF - Apoptosis
IS - 9-10
ER -