The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

Davaadelger, Batzaya; Perez, Ricardo E.; Zhou, Yalu; Duan, Lei; Gitelis, Steven; Maki, Carl G.

doi:10.1080/15384047.2017.1345397

Cited by 12 publications

(8 citation statements)

References 41 publications

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“…Interestingly, we observed that treatment of DDLPS with MDM2 antagonists induced an upregulation of RTKs, including IGF-1R and PDGFRβ. These results are in line with those of previous studies showing that nutlin increased activation of RTKs such as IGF-1R in other tumor models [ 32 ]. Immunoblot analysis revealed increased expression of p-ERK along with IGF-1R β in MDM2 inhibitor-treated IB115 and IB111 cells, which was not observed when these cells were co-treated with the ROS scavenger TEMPO.…”

Section: Discussionsupporting

confidence: 93%

MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

Roy

Laroche-Clary

Verbeke

et al. 2020

Cancers

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The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.

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Section: Discussionsupporting

confidence: 93%

MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

Roy

Laroche-Clary

Verbeke

et al. 2020

Cancers

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“…Specifically, we found autophagy was inhibited in response to Nutlin-activated p53 in cell lines that undergo apoptosis in response to Nutlin, but maintained or increased in cell lines that are apoptosis resistant 6 . Chemical inhibitors of autophagy increased apoptosis in Nutlin-treated cells that were otherwise apoptosis resistant, supporting the idea that autophagy inhibition contributes to apoptosis 6,13 . Most importantly, we found that inhibiting glycolysis (e.g.…”

Section: Introductionsupporting

confidence: 56%

“…We previously reported that autophagy is inhibited by Nutlin in cells sensitive to Nutlin-induced apoptosis, but not inhibited or increased in cells resistant to apoptosis 6,13 . Inhibition of autophagy increased apoptosis in response to Nutlin, confirming that autophagy promotes apoptosis resistance.…”

Section: Resultsmentioning

confidence: 93%

Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a

Duan

Perez

Maki

2018

Cancer Biology & Therapy

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Activated p53 can promote apoptosis or cell cycle arrest. Differences in energy metabolism can influence cell fate in response to activated p53. Nutlin-3a is a preclinical drug and small molecule activator of p53. Alpha-ketoglutarate (αKG) levels were reduced in cells sensitive to Nutlin-3a-induced apoptosis and increased in cells resistant to this apoptosis. Add-back of a cell-permeable αKG analog (DMKG) rescued cells from apoptosis in response to Nutlin-3a. OGDH is a component of the αKGDH complex that converts αKG to succinate. OGDH knockdown increased endogenous αKG levels and also rescued cells from Nutlin-3a-induced apoptosis. We previously showed reduced autophagy and ATG gene expression contributes to Nutlin-3a-induced apoptosis. DMKG and OGDH knockdown restored autophagy and ATG gene expression in Nutlin-3a-treated cells. These studies indicate αKG levels, regulated by p53 and OGDH, determine autophagy and apoptosis in response to Nutlin-3a. ARTICLE HISTORY

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“…CPPD resistant cell lines also show increased activity of IGF1R/AKT signaling. Inhibitors of IGF1R or AKT induced apoptosis in CPPD-resistant cell lines in combination with Nutlin-3 by increasing p53 levels and inhibiting pro-survival autophagy [ 400 ]. UT-SSC26A is a cell line with enhanced chemoresistance to CPPD, it expresses a truncated p53 [ 401 ].…”

Section: Therapy Targeting P53mentioning

confidence: 99%

p53 and metabolism: from mechanism to therapeutics

et al. 2018

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The tumor cell changes itself and its microenvironment to adapt to different situations, including action of drugs and other agents targeting tumor control. Therefore, metabolism plays an important role in the activation of survival mechanisms to keep the cell proliferative potential. The Warburg effect directs the cellular metabolism towards an aerobic glycolytic pathway, despite the fact that it generates less adenosine triphosphate than oxidative phosphorylation; because it creates the building blocks necessary for cell proliferation. The transcription factor p53 is the master tumor suppressor; it binds to more than 4,000 sites in the genome and regulates the expression of more than 500 genes. Among these genes are important regulators of metabolism, affecting glucose, lipids and amino acids metabolism, oxidative phosphorylation, reactive oxygen species (ROS) generation and growth factors signaling. Wild-type and mutant p53 may have opposing effects in the expression of these metabolic genes. Therefore, depending on the p53 status of the cell, drugs that target metabolism may have different outcomes and metabolism may modulate drug resistance. Conversely, induction of p53 expression may regulate differently the tumor cell metabolism, inducing senescence, autophagy and apoptosis, which are dependent on the regulation of the PI3K/AKT/mTOR pathway and/or ROS induction. The interplay between p53 and metabolism is essential in the decision of cell fate and for cancer therapeutics.

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The IGF-1R/AKT pathway has opposing effects on Nutlin-3a-induced apoptosis

Cited by 12 publications

References 41 publications

MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a

p53 and metabolism: from mechanism to therapeutics

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