Translational control by oncogenic signaling pathways

Gao, Beichen; Roux, Philippe P.

doi:10.1016/j.bbagrm.2014.11.006

Cited by 44 publications

(43 citation statements)

References 236 publications

(315 reference statements)

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“…To further validate that mammosphere formation is functionally dependent on protein synthesis, we next used a well-established FDA-approved drug that potently inhibits protein synthesis, namely rapamycin [21-23]. Figure 6 shows the effects of increasing concentrations of rapamycin on mammosphere formation.…”

Section: Resultsmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than “bulk” cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.

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Section: Resultsmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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“…1E and 2B). Cells expressing mutant K-Ras have previously been shown to have higher rates of protein synthesis compared to K-Ras WT cells (Gao and Roux, 2015). Recently we showed that cancer cell lines that have activated PI3K pathways have higher rates of general protein synthesis and protein turnover and become impaired if either pathway is perturbed, while isogenic cells without activated PI3K are much less sensitive (Davoli et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells

et al. 2017

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Summary Activating mutations in the KRAS oncogene are highly prevalent in tumors, especially those of the colon, lung, and pancreas. To better understand the genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss of function screens in two isogenic pairs of cell lines. Since loss of essential genes is uniformly toxic in CRISPR-based screens we also developed an shRNA library targeting essential genes. These approaches uncovered a large set of proteins whose loss results in the selective reduction of K-Ras mutant cell growth. Pathway analysis revealed that many of these genes function in the mitochondria. For validation, we generated isogenic pairs of cell lines using CRISPR-based genome engineering, which confirmed the dependency of K-Ras mutant cells on these mitochondrial pathways. Finally, we found that mitochondrial inhibitors reduce the growth of K-Ras mutant tumors in vivo, advancing strategies to target K-Ras-driven malignancy.

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“…Indeed, most kinases have multiple cellular substrates, and a wide variety of cellular processes undergo kinase-based regulation including gene transcription and translation [see for examples (Gao and Roux, 2015; Thapar and Denmon, 2013; Whitmarsh, 2007)], channel functionality (Chahine and O’Leary, 2014), cytoskeleton organization (Rudrabhatla, 2014), and intracellular trafficking of proteins and cellular organelles (Gibbs et al, 2015; Morfini et al, 2009a). As discussed below, a cellular process affected by deregulated kinases with particular relevance for AOND pathogenesis may be AT.…”

Section: Introductionmentioning

confidence: 99%

Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

Brady

Morfini

2017

Neurobiology of Disease

119

123

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Neurons affected in a wide variety of unrelated adult-onset neurodegenerative diseases (AONDs) typically exhibit a “dying back” pattern of degeneration, which is characterized by early deficits in synaptic function and neuritic pathology long before neuronal cell death. Consistent with this observation, multiple unrelated AONDs including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and several motor neuron diseases feature early alterations in kinase-based signaling pathways associated with deficits in axonal transport (AT), a complex cellular process involving multiple intracellular trafficking events powered by microtubule-based motor proteins. These pathogenic events have important therapeutic implications, suggesting that a focus on preservation of neuronal connections may be more effective to treat AONDs than addressing neuronal cell death. While the molecular mechanisms underlying AT abnormalities in AONDs are still being analyzed, evidence has accumulated linking those to a well-established pathological hallmark of multiple AONDs: altered patterns of neuronal protein phosphorylation. Here, we present a short overview on the biochemical heterogeneity of major motor proteins for AT, their regulation by protein kinases, and evidence revealing cell type-specific AT specializations. When considered together, these findings may help explain how independent pathogenic pathways can affect AT differentially in the context of each AOND.

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Translational control by oncogenic signaling pathways

Cited by 44 publications

References 236 publications

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells

Regulation of motor proteins, axonal transport deficits and adult-onset neurodegenerative diseases

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