PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis

Gu, Juan; Wang, Zeping; Reeves, Raymond; Magnuson, Nancy S.

doi:10.1038/onc.2009.276

Cited by 95 publications

(67 citation statements)

References 41 publications

(64 reference statements)

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“…phosphorylating the inhibitory site Ser83 on ASK1 (25), and PIM1 has been correlated with tumor aggressiveness and poor survival in TNBC (62). Combining NOS inhibition therapy with docetaxel may prevent activation of PIM1, resulting in a decrease of pASK1 Ser83 levels and an increase in pASK1 Thr845 levels, which result in activation of effector proteins JNK and cleaved caspases 3 and 9 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, phosphorylation of Thr845 ASK1 is essential for ASK1 activation, which promotes apoptotic cell death (23). Ser83 remains phosphorylated under low-stress conditions, keeping ASK1 inactive (24,25). Ser967 serves as a sensor that mediates the physical interaction of 14-3-3 with ASK1, which suppresses ASK1-mediated apoptosis (22,26).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Dávila‐González

Choi

Rosato

et al. 2018

Clinical Cancer Research

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Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC.Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition þ docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay.Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9.Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Dávila‐González

Choi

Rosato

et al. 2018

Clinical Cancer Research

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“…24 Phosphorylation at Ser-83 is known to be catalyzed by Akt or PIM1. 27,29 Oligomerization-dependent autophosphorylation at Thr-838, which is located in the activation loop of the kinase domain, is essential for ASK1 activation. 14,18,30 Phosphorylation at Tyr-718 by JAK2 induces ASK1 degradation.…”

mentioning

confidence: 99%

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

Cho

Park

et al. 2015

Cell Death Differ

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Cdc25C (cell division cycle 25C) phosphatase triggers entry into mitosis in the cell cycle by dephosphorylating cyclin B-Cdk1. Cdc25C exhibits basal phosphatase activity during interphase and then becomes activated at the G 2 /M transition after hyperphosphorylation on multiple sites and dissociation from 14-3-3. Although the role of Cdc25C in mitosis has been extensively studied, its function in interphase remains elusive. Here, we show that during interphase Cdc25C suppresses apoptosis signal-regulating kinase 1 (ASK1), a member of mitogen-activated protein (MAP) kinase kinase kinase family that mediates apoptosis. Cdc25C phosphatase dephosphorylates phospho-Thr-838 in the activation loop of ASK1 in vitro and in interphase cells. In addition, knockdown of Cdc25C increases the activity of ASK1 and ASK1 downstream targets in interphase cells, and overexpression of Cdc25C inhibits ASK1-mediated apoptosis, suggesting that Cdc25C binds to and negatively regulates ASK1. Furthermore, we showed that ASK1 kinase activity correlated with Cdc25C activation during mitotic arrest and enhanced ASK1 activity in the presence of activated Cdc25C resulted from the weak association between ASK1 and Cdc25C. In cells synchronized in mitosis following nocodazole treatment, phosphorylation of Thr-838 in the activation loop of ASK1 increased. Compared with hypophosphorylated Cdc25C, which exhibited basal phosphatase activity in interphase, hyperphosphorylated Cdc25C exhibited enhanced phosphatase activity during mitotic arrest, but had significantly reduced affinity to ASK1, suggesting that enhanced ASK1 activity in mitosis was due to reduced binding of hyperphosphorylated Cdc25C to ASK1. These findings suggest that Cdc25C negatively regulates proapoptotic ASK1 in a cell cycle-dependent manner and may play a role in G 2 /M checkpointmediated apoptosis.

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“…The molecular mechanisms by which PIM kinases regulate cell proliferation may include the inactivation of cell cycle inhibitors p27 Kip1 (13) or p21 cip1 (14) or the activation of molecules that positively regulate cell cycle progression, such as CDC25A, CDC25C, or the kinase C-TAK1 (15). PIM kinases also regulate cell viability by phosphorylating the apoptotic proteins BAD and ASK1 (16,17). Regulation of gene transcription by PIM kinases through interactions with c-myc, c-myb, and NFATc (15,18) may also play a role in the regulation of cell proliferation and viability.…”

Section: Introductionmentioning

confidence: 99%

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

Chang

Kanwar

Feng

et al. 2010

Molecular Cancer Therapeutics

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Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC 50 s of 0.6 to 0.9 μmol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 μmol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3 , we used PIM-1-, PIM-2-, or PIM-3-specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3 Tyr705. The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3 Tyr705 . These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3 Tyr705

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PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis

Cited by 95 publications

References 41 publications

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

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