Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Lalaoui, Najoua; Hänggi, Kay; Brumatti, Gabriela; Chau, Diep; Nguyen, Nhu; Vasilikos, Lazaros; Spilgies, Lisanne M.; Heckmann, Denise A.; Ma, Chunyan; Ghisi, Margherita; Salmon, Jessica M.; Matthews, Geoffrey M.; Valle, Elisha de; Moujalled, Donia; Menon, Manoj B.; Spall, Sukhdeep K; Glaser, Stefan; Richmond, Jennifer; Lock, Richard B.; Condon, Stephen M.; Gugasyan, Raffi; Gaestel, Matthias; Guthridge, Mark A.; Johnstone, Ricky W.; Munoz, Lenka; Wei, Andrew H.; Ekert, Paul G.; Vaux, David L.; Wong, Wendy Wei-Lynn

doi:10.1016/j.ccell.2016.08.009

Cited by 32 publications

(43 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4b and Additional file 1: Figure S4A). Importantly, we find that these conditions lead to phosphorylation and activation of p38 MAPK and its downstream effector, MAPKAPK2 (MK2) [67,68] ( Fig. 4b).…”

Section: The P38 Mapk-mk2 Pathway Phosphorylates Ttp To Promote Exprementioning

confidence: 79%

“…These include: 1. DNA damage ATM [63][64][65] and stress activated p38 MAPK that in turn promotes MK2 [67,68], to post-transcriptionally upregulate ARE-bearing mRNAs [59,61,62]. The expressed mRNAs include ARE-bearing pro-inflammatory cytokine TNFα [73,74] & its receptors that activates downstream anti-apoptosis signals (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To examine whether the p38 MAPK-MK2 pathway phosphorylates TTP in resistant G0 leukemic cells, two different inhibitors of p38 MAPK were tested. Treatment with p38 MAPKα/β inhibitor, LY2228820 (LY) [68,69], or a pan-p38 MAPK inhibitor that targets all isoforms, BIRB796 (BIRB) [70], blocked phosphorylation of MK2 and prevented MK2mediated TTP phosphorylation and reduces TNFα in AraCS cells (Fig. 4c).…”

Section: The P38 Mapk-mk2 Pathway Phosphorylates Ttp To Promote Exprementioning

confidence: 95%

“…Conversely, even low concentrations of BIRB were sufficient to reduce chemoresistance (Additional file 1: Figure S4C). Unlike in solid tumors, where activation of p38 MAPK-MK2 induces resistance by arresting the cell cycle [30,67,68], p38 MAPK inhibition did not affect the cell cycle in AML cells (Additional file 1: Figure S4D). These data uncover rapid activation of a p38 MAPK-MK2 pathway that enables chemosurvival of G0 leukemic cells via inhibition of TTP activity.…”

Section: Phosphorylation Of Ttp Induced By P38 Mapk-mk2 Promotes Chemmentioning

confidence: 96%

“…TNFα can also be inhibited pharmacologically with the drug pirfenidone (PFD) that can block TNFα translation in RAW264.7 cells and is used to treat idiopathic pulmonary fibrosis [68,71,72]. In G0 leukemic cells, PFD reduced TNFα translatome and protein levels but not mRNA levels ( Fig.…”

Section: Tnfα Induced By Phosphorylation Of Ttp Promotes Chemoresismentioning

confidence: 99%

See 4 more Smart Citations

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells

et al. 2020

View full text Add to dashboard Cite

Background: Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown. Results:We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo.Conclusions: These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE-bearing mRNAs that promote chemoresistance. By disrupting this pathway, we develop an effective combination therapy against chemosurvival.

show abstract

Section: The P38 Mapk-mk2 Pathway Phosphorylates Ttp To Promote Exprementioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: The P38 Mapk-mk2 Pathway Phosphorylates Ttp To Promote Exprementioning

confidence: 95%

Section: Phosphorylation Of Ttp Induced By P38 Mapk-mk2 Promotes Chemmentioning

confidence: 96%

Section: Tnfα Induced By Phosphorylation Of Ttp Promotes Chemoresismentioning

confidence: 99%

See 3 more Smart Citations

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells

et al. 2020

View full text Add to dashboard Cite

show abstract

Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Ray

Berggren

Cruz

et al. 2017

Intl Journal of Cancer

View full text Add to dashboard Cite

Colorectal cancer (CRC) development and progression is associated with chronic inflammation. We have identified the MAPK-activated protein kinase 2 (MK2) pathway as a primary mediator of inflammation in CRC. MK2 signaling promotes production of proinflammatory cytokines IL-1β, IL-6 and TNF-α. These cytokines have been implicated in tumor growth, invasion and metastasis. For the first time, we investigate whether MK2 inhibition can improve outcome in two mouse models of CRC. In our azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated CRC, MK2 inhibitor treatment eliminated murine tumor development. Using the implanted, syngeneic murine CRC cell line CT26, we observe significant tumor volume reduction following MK2 inhibition. Tumor cells treated with MK2 inhibitors produced 80% less IL-1β, IL-6 and TNF-α and demonstrated decreased invasion. Replenishment of downstream proinflammatory MK2-mediated cytokines (IL-1β, IL-6 and TNF-α) to tumors led to restoration of tumor proliferation and rapid tumor regrowth. These results demonstrate the importance of MK2 in driving proinflammatory cytokine production, its relevance to in vivo tumor proliferation and invasion. Inhibition of MK2 may represent an attractive therapeutic target to suppress tumor growth and progression in patients.

show abstract

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

et al. 2019

View full text Add to dashboard Cite

In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and nonapoptotic processes. We previously showed that IAP inhibition induced a loss of stemness and glioblastoma stem cells differentiation by activating nuclear factor‐κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastoma stem‐like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC‐0152, a small‐molecule IAPs inhibitor, triggered stem‐like cell apoptosis and decreased proliferation in four human glioblastoma cell lines. We set up a three‐dimensional glioblastoma spheroid model in which time‐of‐flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein+ cells at their periphery. These oxygen‐dependent GDC‐0152 antitumoral effects have been confirmed on human glioblastoma explants. Notably, serine–threonine kinase activation analysis revealed that under hypoxic conditions, IAP inhibition activated ataxia telangiectasia and Rad3‐related protein signaling. Our findings provide new insights into the dual mechanism of action of IAP inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019;37:731–742

show abstract

Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Cited by 32 publications

References 0 publications

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells

Inhibition of MK2 suppresses IL‐1β, IL‐6, and TNF‐α‐dependent colorectal cancer growth

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner

Contact Info

Product

Resources

About