JNK inhibition blocks piperlongumine-induced cell death and transcriptional activation of heme oxygenase-1 in pancreatic cancer cells

Mohammad, Jiyan; Singh, Rajesh; Riggle, Cody; Haugrud, Brandon; Abdalla, Maher Y.; Reindl, Katie M.

doi:10.1007/s10495-019-01553-9

Cited by 35 publications

(30 citation statements)

References 55 publications

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“…Previously, we showed that the interaction between JNK and GSTP1 is interrupted in PDAC cells treated with a GSTP1 inhibitor [39]. Additionally, complementing our current results, it was shown that a JNK inhibitor could restore viability of PDAC cells treated with a GSTP1 inhibitor [39]. As expected, GSTP1 knockdown increased the expression of phosphorylated JNK and its downstream target, c-Jun, in PDAC cells.…”

Section: Discussionsupporting

confidence: 90%

“…However, under oxidative stress conditions, GSTP1 dimerizes into aggregates and its binding to JNK is deterred, enabling JNK activation [38]. Previously, we showed that the interaction between JNK and GSTP1 is interrupted in PDAC cells treated with a GSTP1 inhibitor [39]. Additionally, complementing our current results, it was shown that a JNK inhibitor could restore viability of PDAC cells treated with a GSTP1 inhibitor [39].…”

Section: Discussionsupporting

confidence: 87%

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Glutathione S-Transferase pi-1 Knockdown Reduces Pancreatic Ductal Adenocarcinoma Growth by Activating Oxidative Stress Response Pathways

Singh

Mohammad

Orr

et al. 2020

Cancers

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Glutathione S-transferase pi-1 (GSTP1) plays an important role in regulating oxidative stress by conjugating glutathione to electrophiles. GSTP1 is overexpressed in breast, colon, lung, and prostate tumors, where it contributes to tumor progression and drug resistance; however, the role of GSTP1 in pancreatic ductal adenocarcinoma (PDAC) is not well understood. Using shRNA, we knocked down GSTP1 expression in three different PDAC cell lines and determined the effect on cell proliferation, cell cycle progression, and reactive oxygen species (ROS) levels. Our results show GSTP1 knockdown reduces PDAC cell growth, prolongs the G0/G1 phase, and elevates ROS in PDAC cells. Furthermore, GSTP1 knockdown results in the increased phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the decreased phosphorylation of extracellular signal-regulated kinase (ERK), p65, the reduced expression of specificity protein 1 (Sp1), and the increased expression of apoptosis-promoting genes. The addition of the antioxidant glutathione restored cell viability and returned protein expression levels to those found in control cells. Collectively, these data support the working hypothesis that the loss of GSTP1 elevates oxidative stress, which alters mitogen-activated protein (MAP) kinases and NF-κB signaling, and induces apoptosis. In support of these in vitro data, nude mice bearing orthotopically implanted GSTP1-knockdown PDAC cells showed an impressive reduction in the size and weight of tumors compared to the controls. Additionally, we observed reduced levels of Ki-67 and increased expression of cleaved caspase-3 in GSTP1-knockdown tumors, suggesting GSTP1 knockdown impedes proliferation and upregulates apoptosis in PDAC cells. Together, these results indicate that GSTP1 plays a significant role in PDAC cell growth and provides support for the pursuit of GSTP1 inhibitors as therapeutic agents for PDAC.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 87%

Glutathione S-Transferase pi-1 Knockdown Reduces Pancreatic Ductal Adenocarcinoma Growth by Activating Oxidative Stress Response Pathways

Singh

Mohammad

Orr

et al. 2020

Cancers

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“…However, others have reported no impact of metalloporphyrins on HMOX1 protein levels in human breast cancer cells in vitro (Lin, Shen, Hou, Yang, & Chen, 2008) or DBA/1J mice in vivo (Devesa et al., 2005 ) . Additionally, ZnPP, but not SnPP, has been reported to cause a compensatory upregulation (mRNA and protein) of HMOX1 in human pancreatic cancer cells (Mohammad et al., 2019) and hamster fibroblasts (Yang et al., 2001). Taken together, the compensatory effect of metalloporphyrins on HMOX1 expression may be cell line‐, tissue‐ or species‐dependent and there is some evidence that SnPP may be a more modest inducer of HMOX1 expression than ZnPP.…”

Section: Resultsmentioning

confidence: 99%

“…*p < .05, **p < .01, ***p < .001 DBA/1J mice in vivo (Devesa et al, 2005). Additionally, ZnPP, but not SnPP, has been reported to cause a compensatory upregulation (mRNA and protein) of HMOX1 in human pancreatic cancer cells (Mohammad et al, 2019) and hamster fibroblasts (Yang et al, 2001).…”

Section: Nrf2 and Hmox1 Are Important For Melanosphere Formation Inmentioning

confidence: 98%

Heme oxygenase promotes B‐Raf‐dependent melanosphere formation

Jasmer

Hou

Mannino

et al. 2020

Pigment Cell Melanoma Res

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“…In the tumor environment, cancer cells undergo proto-oncogene transformation, and the JNK signaling pathway is usually activated and plays an important role in carcinogenesis and progression [27][28][29]. GSTP1 is a natural inhibitor of the JNK signaling pathway through binding to the carboxyl terminal negative charge region of the JNK protein [14,16,30]. Compared with the GSTP1 dimer, the GSTP1 monomer has higher JNK protein binding activity.…”

Section: Discussionmentioning

confidence: 99%

Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

Fang

et al. 2020

Preprint

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Background PCSK9 has been found to be closely related to the occurrence and development of a variety of tumors. However, the concrete role of PCSK9 and its relationship with HCC development is largely unknown. Methods The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry assays. The effects of PCSK9 expression on HCC biological traits were investigated by overexpressing and downregulating PCSK9 protein in vivo and in vitro. The mechanism by which PCSK9 mediates the depolymerization of the GSTP1 dimer and the phosphorylation of the JNK signaling pathway was further investigated. Results PCSK9 is downregulated in human HCC tissues. HCC cell proliferation, cell cycle phase distribution and apoptosis were inhibited by PCSK9 in vitro. PCSK9 suppresses tumor growth and metastasis of HCC in vivo. PCSK9 interacts with GSTP1 and promotes the depolymerization of the GSTP1 dimer and inactivation of the JNK signaling pathway. Furthermore, low PCSK9 protein expression in primary HCC tissues correlated with worse clinical outcomes. Conclusions PCSK9 inhibits HCC cell proliferation, cell cycle phase distribution and apoptosis by interacting with GSTP1 and suppressing the JNK signaling pathway, suggesting that PCSK9 might act as a tumor suppressor and may serve as a therapeutic target for the treatment of HCC.

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JNK inhibition blocks piperlongumine-induced cell death and transcriptional activation of heme oxygenase-1 in pancreatic cancer cells

Cited by 35 publications

References 55 publications

Glutathione S-Transferase pi-1 Knockdown Reduces Pancreatic Ductal Adenocarcinoma Growth by Activating Oxidative Stress Response Pathways

Glutathione S-Transferase pi-1 Knockdown Reduces Pancreatic Ductal Adenocarcinoma Growth by Activating Oxidative Stress Response Pathways

Heme oxygenase promotes B‐Raf‐dependent melanosphere formation

Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

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