Inhibitions of mTORC1 and 4EBP-1 are key events orchestrated by Rottlerin in SK-Mel-28 cell killing

Daveri, Elena; Maellaro, Emilia; Valacchi, Giuseppe; Ietta, Francesca; Muscettola, Michela; Maioli, Emanuela

doi:10.1016/j.canlet.2016.06.018

Cited by 9 publications

(11 citation statements)

References 31 publications

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“…In our earlier study on SK‐Mel‐28 melanoma cells, we found that rottlerin killed this highly chemoresistant cell line through a nonconventional mechanism (nonapoptotic, nonnecroptotic, and nonautophagic) based on mammalian target of rapamycin complex 1/eukaryotic translation initiation factor 4E‐binding protein 1 (mTORC1/4EBP1) inhibition and consequent suppression of protein translation . This result revealed an additional mechanism of toxicity that could be more generalized than previously recognized.…”

Section: Introductionmentioning

confidence: 79%

“…The bulk of its activity is directed to arrest cancer progression, by the employment of key signaling pathways that control proliferation, migration/invasion, and autophagic and/or apoptotic cell death. Very recently, we found a novel anticancer mechanism in SK‐Mel 28 melanoma cells, based on the shutoff of the translational apparatus …”

Section: Discussionmentioning

confidence: 99%

“…The incorporation of puromycin, which becomes covalently linked to the C-terminus of the nascent polypeptides, was used to label newly synthesized proteins, in order to monitor protein synthesis, as previously described. 22 In A375 cells treated for 6-24 hr with 20 μM rottlerin, puromycin was added to the medium (1 μg/mL) just 10 min before the end of the experiment. After two washes with PBS, cells were lysed and the labeled polypeptides were visualized by Western blotting analysis using an anti-puromycin polyclonal antibody.…”

Section: Measurement Of Proteosynthesismentioning

confidence: 99%

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Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells

et al. 2019

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Rottlerin is a cytostatic and cytotoxic drug in a variety of cancer cells. Our previous experience demonstrated that depending upon the genetic/biochemical background of cancer cells, rottlerin is able to induce both apoptotic and autophagic cell death, or dramatically disturb protein homeostasis leading to lethal cellular atrophy. In the current study, we investigated the cytotoxic effects and mechanisms of rottlerin against human amelanotic A375 melanoma cells. In this cell line, rottlerin exhibits its main and newest cytotoxic properties, that is, growth arrest, apoptosis induction, and translation shutoff. In fact, the drug, time‐, and dose‐dependently, markedly inhibited cell proliferation through cyclin D1 downregulation and induced apoptotic cell death as early as after 18 h treatment. Mechanistically, rottlerin triggered apoptosis by both intrinsic and extrinsic pathways. Both pathways are likely activated by the downregulation of the antiapoptotic B‐cell lymphoma 2 (Bcl‐2) protein, which simultaneously affects mitochondrial and endoplasmic reticulum (ER) membranes stability. Concomitantly to extrinsic apoptosis induction, the rottlerin‐activated ER stress/eukaryotic initiation factor 2 (eIF2) α axis blocked the translational apparatus. The altered proteostasis precluded the complete cells' rescue from death in the presence of apoptosis inhibitors.

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Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Measurement Of Proteosynthesismentioning

confidence: 99%

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Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells

et al. 2019

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“…Some studies have indicated that rottlerin decrease carcinogenesis by impacting the mammalian target of rapamycin complex 1 (mTORC1) signaling [27]. Furthermore, rottlerin inhibits the markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8), and metastasis (MMP-2 and MMP-9), thus blocking production of tumorigenic mediators in the tumor microenvironment [28].…”

Section: Discussionmentioning

confidence: 99%

Rottlerin as a novel chemotherapy agent for adrenocortical carcinoma

et al. 2017

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Adrenocortical carcinoma (ACC) is a rare, but aggressive endocrine malignancy with a generally poor clinical outcome. There is no effective therapy for advanced and metastatic ACC. In our study, we found that an existing drug (rottlerin) exerted its tumour-suppressive function in ACC. Specifically, rottlerin inhibited cellular proliferation of ACC cell lines (NCI-H295R and SW-13) in a dose- and time-dependent manner. We also found that rottlerin induced cell apoptosis and promoted G0/G1 cell cycle arrest in ACC cell lines. The cellular migration and invasion of ACC cell lines were decreased after treatment with rottlerin. Further, the molecular expression of lipoprotein receptor related protein 6 (LRP6) and β-catenin were down-regulated in rottlerin-treated ACC cells, which indicated that Wnt/β-catenin signaling was involved in the tumour-suppressive function of rottlerin. To further confirm the anti-tumour function of rottlerin, a nude mouse ACC xenograft model was used. The xenograft growth curves and TUNEL assays demonstrated that rottlerin inhibited proliferation and induced apoptosis in the ACC xenograft model. Furthermore, we verified that rottlerin down-regulated the expression of LRP6 and β-catenin in vivo. The ACC cell line and xenograft mouse model data indicated that rottlerin significantly inhibited proliferation and induced apoptosis of ACC cells, likely via suppression of the Wnt/β-catenin signaling pathway. Our study indicated the potential therapeutic utility of rottlerin as a novel and potential chemotherapeutic agent for ACC.

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“…Attenuation of the mTOR signaling pathway contributes to PRRSV-induced host translation shutoff. mTOR is thought to modulate protein synthesis, and mTOR inhibition causes the almost-complete arrest of protein synthesis (43,44). To determine how the attenuation of the mTOR signaling pathway affects translation in PRRSV-…”

Section: Prrsv Infection Induces Translation Suppression In Cellsmentioning

confidence: 99%

Porcine Reproductive and Respiratory Syndrome Virus Infection Induces both eIF2α Phosphorylation-Dependent and -Independent Host Translation Shutoff

Fang

Zhou

et al. 2018

J Virol

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Porcine reproductive and respiratory syndrome virus (PRRSV) is an that has caused tremendous economic losses in the global swine industry since it was discovered in the late 1980s. Inducing host translation shutoff is a strategy used by many viruses to optimize their replication and spread. Here, we demonstrate that PRRSV infection causes host translation suppression, which is strongly dependent on viral replication. By screening PRRSV-encoded nonstructural proteins (nsps), we found that nsp2 participates in the induction of host translation shutoff and that its transmembrane (TM) domain is required for this process. nsp2-induced translation suppression is independent of protein degradation pathways and the phosphorylation of eukaryotic initiation factor 2α (eIF2α). However, the overexpression of nsp2 or its TM domain significantly attenuated the mammalian target of rapamycin (mTOR) signaling pathway, an alternative pathway for modulating host gene expression. PRRSV infection also attenuated the mTOR signaling pathway, and PRRSV-induced host translation shutoff could be partly reversed when the attenuated mTOR phosphorylation was reactivated by an activator of the mTOR pathway. PRRSV infection still negatively regulated the host translation when the effects of eIF2α phosphorylation were completely reversed. Taken together, our results demonstrate that PRRSV infection induces host translation shutoff and that nsp2 is associated with this process. Both eIF2α phosphorylation and the attenuation of the mTOR signaling pathway contribute to PRRSV-induced host translation arrest. Viruses are obligate parasites, and the production of progeny viruses relies strictly on the host translation machinery. Therefore, the efficient modulation of host mRNA translation benefits viral replication, spread, and evolution. In this study, we provide evidence that porcine reproductive and respiratory syndrome virus (PRRSV) infection induces host translation shutoff and that the viral nonstructural protein nsp2 is associated with this process. Many viruses induce host translation shutoff by phosphorylating eukaryotic initiation factor 2α (eIF2α). However, PRRSV nsp2 does not induce eIF2α phosphorylation but attenuates the mTOR signaling pathway, another pathway regulating the host cell translational machinery. We also found that PRRSV-induced host translation shutoff was partly reversed by eliminating the effects of eIF2α phosphorylation or reactivating the mTOR pathway, indicating that PRRSV infection induces both eIF2α phosphorylation-dependent and -independent host translation shutoff.

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Inhibitions of mTORC1 and 4EBP-1 are key events orchestrated by Rottlerin in SK-Mel-28 cell killing

Cited by 9 publications

References 31 publications

Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells

Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells

Rottlerin as a novel chemotherapy agent for adrenocortical carcinoma

Porcine Reproductive and Respiratory Syndrome Virus Infection Induces both eIF2α Phosphorylation-Dependent and -Independent Host Translation Shutoff

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