Activation of Ras/PI3K/ERK Pathway Induces c-Myc Stabilization to Upregulate Argininosuccinate Synthetase, Leading to Arginine Deiminase Resistance in Melanoma Cells

Tsai, Wen Bin; Aiba, Isamu; Long, Yan; Lin, Hui Kuan; Feun, Lynn G.; Savaraj, Niramol; Kuo, M. Tien

doi:10.1158/0008-5472.can-11-3605

Cited by 179 publications

(208 citation statements)

References 49 publications

(53 reference statements)

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“…We further demonstrated that upregulation of c-Myc follows the signal transduction mechanism involving Ras→PI3K/Akt/ERK→GSK3β, where ERK phosphorylates c-Myc, resulting in c-Myc accumulation by suppressing proteasomal degradation 59 . However, how Arg-auxotrophic stress is sensed in activating the Ras signal is not known.…”

Section: Introductionmentioning

confidence: 69%

“…To investigate whether activation of receptor tyrosine kinases (RTK) is involved in Arg-auxotrophic response that activates Ras signaling 59 , we used lysates of A2058 cells treated with or without ADI for 15 min to probe an array of 42 anti-phosphotyrosine receptor antibodies in duplicate and observed that Axl was the predominant RTK activated (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

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Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

et al. 2015

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Many human malignancies lack de novo biosynthesis of arginine (Arg) because the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate early event of Arg-auxotrophic response involves ROS-mediated secretion of Gas6 which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression which feedbacks to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 feedbacks to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response consisting of Axl, c-Myc, ASS1 that regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg deprivation strategies.

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Section: Introductionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

et al. 2015

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“…41 Some PIM responder cell lines identified here are known to harbor oncogenic fusion tyrosine kinases, including BCR-ABL in HNT34, FGFR1OP2-FGFR1 in KG1, and FIP1L1-PDGFRA in EOL1, which may cooperate with PIM kinases to maintain maximum STAT5 activation and prolonged MYC half-life. To evaluate whether these fusion kinases cooperate with PIM to enhance cell growth, we treated BCR-ABL-positive HNT34 cells with the combination of compound C and imatinib.…”

Section: Pim Inhibitors Impede Growth Of Cd25-positive Aml 1781mentioning

confidence: 83%

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Guo

Wang

Zhang

et al. 2014

Blood

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Key Points• CD25 is a predictive biomarker for sensitivity to PIM inhibitors in AML cells.• PIM inhibitors may prolong overall/relapse-free survival through attenuating STAT5 activation and destabilizing MYC in CD25 1 AML cells.Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in

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“…The hypothetical effector involved in c-Myc upregulation could act either directly or indirectly via manipulation of the many pathways Toxoplasma infection is known to impact, such as STAT-3 (1, 47), NF-B (15,48), PI3 kinase (49,50), and MAP kinases (36,39,51). Our results with the ROP16, GRA15, and GRA24 knockouts indicate that these effectors are not responsible for the Toxoplasma-dependent c-Myc induction, suggesting that STAT-3, NF-B, and p38 MAP kinase are not involved in c-Myc induction in infected cells.…”

Section: Discussionmentioning

confidence: 99%

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

2014

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Toxoplasma gondii infection has previously been described to cause dramatic changes in the host transcriptome by manipulating key regulators, including STATs, NF-B, and microRNAs. Here, we report that Toxoplasma tachyzoites also mediate rapid and sustained induction of another pivotal regulator of host cell transcription, c-Myc. This induction is seen in cells infected with all three canonical types of Toxoplasma but not the closely related apicomplexan parasite Neospora caninum. Coinfection of cells with both Toxoplasma and Neospora still results in an increase in the level of host c-Myc, showing that c-Myc is actively upregulated by Toxoplasma infection (rather than repressed by Neospora). We further demonstrate that this upregulation may be mediated through c-Jun N-terminal protein kinase (JNK) and is unlikely to be a nonspecific host response, as heat-killed Toxoplasma parasites do not induce this increase and neither do nonviable parasites inside the host cell. Finally, we show that the induced c-Myc is active and that transcripts dependent on its function are upregulated, as predicted. Hence, c-Myc represents an additional way in which Toxoplasma tachyzoites have evolved to specifically alter host cell functions during intracellular growth.T oxoplasma gondii is a ubiquitous parasite that infects and reproduces in virtually any nucleated cell of warm-blooded animals. It is of great medical importance as infections in immunocompromised humans often lead to life-threatening disease. The ability of Toxoplasma to replicate in a wide host range is likely dependent on the capacity of the parasite to regulate conserved host cell pathways via its secreted factors. For example, the secreted protein ROP16 regulates immunologically important host transcription factors, STAT3 (1), STAT6 (2), and STAT5 (3), causing profound transcriptional changes shortly after invasion. Although many of the changes observed in infected host cells are strain specific and are important for the differences in virulence between the major strains of Toxoplasma (4), it is likely that there is also remodeling of host cells that occurs independently of strain type. Parasite effectors whose function is conserved across the three major types of Toxoplasma (e.g., Toxoplasma protein GRA16, which regulates the host p53 pathway [5]) have previously been identified. Such is likely an effective solution for those instances where the same need is faced by all strains, e.g., disarming defenses common to many hosts and/or meeting a survival challenge encountered in all cells.We have previously reported that infection with Toxoplasma tachyzoites specifically upregulates microRNAs that belong to transcriptional loci miR-17ϳ92 and miR-106bϳ25 (6). These microRNAs play an important role in the cell cycle and apoptosis of a host cell (7) and thereby likely affect the interplay between host and parasite. It has been reported that c-Myc is a direct transcriptional regulator of miR-17ϳ92 and miR-106bϳ25 (8), and so we hypothesized that Toxoplasma induces this tr...

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Activation of Ras/PI3K/ERK Pathway Induces c-Myc Stabilization to Upregulate Argininosuccinate Synthetase, Leading to Arginine Deiminase Resistance in Melanoma Cells

Cited by 179 publications

References 49 publications

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Infection by Toxoplasma gondii Specifically Induces Host c-Myc and the Genes This Pivotal Transcription Factor Regulates

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