Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells

Zhao, Xiaofang; Zhang, Chunyan; Zhou, Hong; Xiao, Bin; Cheng, Ying; Wang, Jinju; Yao, Fuli; Duan, Chunyan; Chen, Run; Li, Youping; Feng, Cheng; Li, Hong; Li, Jing; Dai, Rongyang

doi:10.18632/oncotarget.13408

Cited by 22 publications

(22 citation statements)

References 37 publications

(38 reference statements)

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“…It has been reported that the inactivation of mammalian target of rapamycin (mTOR) is implicated in cell contact inhibition (24). We have previously reported that the mTOR pathway plays an important role in CCA cell growth and survival (25). Here we wonder whether there is a link between c-Myc and mTOR in contact inhibition regulation in CCA cells.…”

Section: Resultsmentioning

confidence: 92%

“…Consistently, our data show that the activity of mTOR decreased obviously in contact-inhibited normal biliary epithelial cells. We and others have previously found that the mTOR pathway is implicated in the carcinogenesis and progression of CCA and mTOR inhibition suppresses the growth of human CCA cells (25,32). Whether the implication of mTOR in CCA is associated with contact inhibition regulation has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

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c-Myc promotes cholangiocarcinoma cells to overcome contact inhibition via the mTOR pathway

Luo

Duan

et al. 2017

Oncology Reports

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The loss of contact inhibition is a hallmark of a wide range of human cancer cells. Yet, the precise mechanism behind this process is not fully understood. c‑Myc plays a pivotal role in carcinogenesis, but its involvement in regulating contact inhibition has not been explored to date. Here, we report that c‑Myc plays an important role in abrogating contact inhibition in human cholangiocarcinoma (CCA) cells. Our data show that the protein level of c‑Myc obviously decreased in contact-inhibited normal biliary epithelial cells. However, CCA cells sustain high protein levels of c‑Myc and keep strong proliferation ability in confluent conditions. Importantly, the suppression of c‑Myc by inhibitor or siRNA induced G0/G1 phase cell cycle arrest in confluent CCA cells. We demonstrate that the inhibition of c‑Myc suppressed the activity of mammalian target of rapamycin (mTOR) in confluent CCA cells, and mTOR inhibition induced G0/G1 phase cell cycle arrest in confluent CCA cells. In confluent CCA cells, the activity of Merlin is downregulated, and Yes-associated protein (YAP) sustains high levels of activity. Furthermore, YAP inhibition not only induced G0/G1 phase cell cycle arrest, but also decreased c‑Myc expression in confluent CCA cells. These results indicate that Merlin/YAP/c‑Myc/mTOR signaling axis promotes human CCA cell proliferation by overriding contact inhibition. We propose that overriding c‑Myc‑mediated contact inhibition is implicated in the development of CCA.

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

c-Myc promotes cholangiocarcinoma cells to overcome contact inhibition via the mTOR pathway

Luo

Duan

et al. 2017

Oncology Reports

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“…Sal is a drug that impairs eIF2α dephosphorylation (42). Studies have reported that Sal increased sensitivity of cancer cell and xenograft tumor models to chemotherapy or rapamycin (28,43,44). 4E1RCat was identified as a molecule capable of impairing eIF4 assembly (20).…”

Section: Discussionmentioning

confidence: 99%

“…The ratio of Sal to 4E1RCat for experimentation was based on the published literature. Specifically, Sal at 1 mg/kg has been used by multiple groups for its ability to inhibit tumor xenografts (28) and other pharmacological activities (29)(30)(31). However, 4E1RCat was not well-studied in mouse models, and hence, the dose of Sal was fixed and 4E1RCat varied to assess and maximize the combined effect.…”

Section: Animal Studiesmentioning

confidence: 99%

Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery

et al. 2020

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Increased protein synthesis is a key process in melanoma, which is regulated by the ALDH18A1 gene encoding pyrroline-5-carboxylate synthase (P5CS). P5CS is involved in proline biosynthesis and targeting ALDH18A1 has previously been shown to inhibit melanoma development by decreasing intracellular proline levels to increase the phosphorylation of eIF2α mediated by GCN2, which then impairs mRNA translation. Since there are no current inhibitors of P5CS, decreased eIF2α phosphorylation in melanoma was targeted using salubrinal (a specific inhibitor of eIF2α phosphatase enzymes). While salubrinal alone was ineffective, the combined use of salubrinal and 4E1RCat (a dual inhibitor of eIF4E:4E-BP1 and eIF4E:eIF4G interaction to prevent assembly of the eIF4F complex and inhibit cap-dependent translation) was found to be effective at decreasing protein synthesis, protein translation, and cell cycle progression to synergistically decrease melanoma cell viability and inhibited xenograft melanoma tumor development. The combination of these agents synergistically decreased melanoma cell viability while having minimal effect on normal cells. This is the first report demonstrating that it is possible to inhibit melanoma viability by targeting eIF2α signaling using salubrinal and 4E1RCat to disrupt assembly of the eIF4F complex.

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“…Salubrinal, a phosphatase inhibitor that represses eIF2α dephosphorylation , is currently in clinical trials in combination with carfilzomib for patients with multiple myeloma (NCT01775553). Further, salubrinal in combination with the mTOR inhibitor rapamycin shows enhanced anti‐tumour activity against cholangiocarcinoma cells . On the other side of the coin, ISRIB (integrated stress response inhibitor) is a small molecule inhibitor identified by cell‐based small molecule screens.…”

Section: Targeting the Translational Machinery In Cancermentioning

confidence: 99%

Translational control of aberrant stress responses as a hallmark of cancer

El-Naggar

Sorensen

2018

The Journal of Pathology

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Altered mRNA translational control is emerging as a critical factor in cancer development and progression. Targeting specific elements of the translational machinery, such as mTORC1 or eIF4E, is emerging as a new strategy for innovative cancer therapy. While translation of most mRNAs takes place through cap-dependent mechanisms, a sub-population of cellular mRNA species, particularly stress-inducible mRNAs with highly structured 5'-UTR regions, are primarily translated through cap-independent mechanisms. Intriguingly, many of these mRNAs encode proteins that are involved in tumour cell adaptation to microenvironmental stress, and thus linked to aggressive behaviour including tumour invasion and metastasis. This necessitates a rigorous search for links between microenvironmental stress and aggressive tumour phenotypes. Under stress, cells block global protein synthesis to preserve energy while maintaining selective synthesis of proteins that support cell survival. One highly conserved mechanism to regulate protein synthesis under cell stress is to sequester mRNAs into cytosolic aggregates called stress granules (SGs), where their translation is silenced. SGs confer survival advantages and chemotherapeutic resistance to tumour cells under stress. Recently, it has been shown that genetically blocking SG formation dramatically reduces tumour invasive and metastatic capacity in vivo. Therefore, targeting SG formation might represent a potential treatment strategy to block cancer metastasis. Here, we present the critical link between selective mRNA translation, stress adaptation, SGs, and tumour progression. Further, we also explain how deciphering mechanisms of selective mRNA translation occurs under cell stress holds great promise for the identification of new targets in the treatment of cancer.

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Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells

Cited by 22 publications

References 37 publications

c-Myc promotes cholangiocarcinoma cells to overcome contact inhibition via the mTOR pathway

c-Myc promotes cholangiocarcinoma cells to overcome contact inhibition via the mTOR pathway

Salubrinal in Combination With 4E1RCat Synergistically Impairs Melanoma Development by Disrupting the Protein Synthetic Machinery

Translational control of aberrant stress responses as a hallmark of cancer

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