Controlling the unfolded protein response-mediated life and death decisions in cancer

Maurel, M.; McGrath, Eoghan P.; Mnich, Katarzyna; Healy, Sandra; Chevet, Éric; Samali, Afshin

doi:10.1016/j.semcancer.2015.03.003

Cited by 88 publications

(95 citation statements)

References 102 publications

(141 reference statements)

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“…However, deregulated or prolonged stress signals can also turn adaptation programs into programed cell death aimed at eliminating irremediably damaged cells. This scenario was demonstrated in the context of several stress pathways including during ER-stress [41]. It is therefore possible that eEF2K integrates signals that promote survival or death depending on the level or duration of its activation status.…”

Section: Discussionmentioning

confidence: 91%

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

et al. 2016

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Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo. Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.

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Section: Discussionmentioning

confidence: 91%

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

et al. 2016

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“…38) Activated ER stress and the UPR could protect cell from cellular injury, but ER stress overload or block in the UPR activation in cells would result in cell apoptosis. 39,40) ER stress can be triggered by various intrinsic or extrinsic factors including accumulation of misfolded proteins, inflammation, hypoxia or nutrient deprivation. And we performed high-content screening (HCS), a high-throughput imaging-based cellular analysis technology that enables the sensitive, detailed detection of multiple parameters simultaneously.…”

Section: Discussionmentioning

confidence: 99%

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Yang

Tang²,

Hao³

et al. 2018

Biological & Pharmaceutical Bulletin

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As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FPinduced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/ Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.

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“…In physiological conditions, these sensors are inactivated by the association with the chaperon protein immunoglobulin-heavy-chain-binding protein (BiP, also known as GRP78). Under severe ER stress, BiP dissociates from the sensors triggering their activation; each of these proteins is coupled with a cytosolic pathway and each pathway converges to apoptosis252627. In particular, transcription factor ATF4, activated by the PERK/eIF2α pathway, stimulates the expression of the proapoptotic protein CHOP (C/EBP homologous protein, also called GADD153).…”

mentioning

confidence: 99%

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Marelli

Marzagalli

Moretti

et al. 2016

Sci Rep

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Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.

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Controlling the unfolded protein response-mediated life and death decisions in cancer

Cited by 88 publications

References 102 publications

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

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