Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Sharma, Divya; Bressler, Kamiko R.; Patel, Harshil; Balasingam, Nirujah; Thakor, Nehal

doi:10.1155/2016/8235121

Cited by 57 publications

(57 citation statements)

References 186 publications

(292 reference statements)

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“…S4A-S4C). EIF2, an enhancer of the translation of specific stress-related mRNA transcripts, has been shown to promote proliferation and survival of cancer cells (25). This is consistent with our functional assays showing increased cell growth of WM4265.2-BrM1 cells both cultured alone ( Fig.…”

Section: Gene-expression Profiling Predicts Ppar Signaling As a Brainsupporting

confidence: 90%

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Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

et al. 2019

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Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is signifi cantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists signifi cantly reduces brain metastatic burden in vivo. Our study clarifi es a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.

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Section: Gene-expression Profiling Predicts Ppar Signaling As a Brainsupporting

confidence: 90%

“…MDA231-BrM cells were generated in Joan Massagué's lab. All these cells have been well characterized by fingerprint or exon sequencing (25,46,47…”

Section: Cell Culturementioning

confidence: 99%

Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

et al. 2019

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“…The sustained levels of iP2-derived transcripts in the absence of detectable levels of protein accumulation may suggest that the translation, as well as transcription, of MIE genes is regulated in a context-dependent manner (e.g., stress-induced translation), consistent with previously established correlates linking cellular stress to viral reactivation (41). For example, the discrete 5′ untranslated regions (UTRs) of the iP-derived transcripts contain multiple alternative AUG translation start sites which may be posited to suppress translational activity via leaky scanning under basal conditions while promoting translation during cell stress (42,43). Such regulatory elements are common in viruses and appear to regulate translation in a similar manner (44)(45)(46).…”

Section: Discussionsupporting

confidence: 80%

Alternative promoters drive human cytomegalovirus reactivation from latency

Collins-McMillen

Rak

Buehler

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Reactivation from latency requires reinitiation of viral gene expression and culminates in the production of infectious progeny. The major immediate early promoter (MIEP) of human cytomegalovirus (HCMV) drives the expression of crucial lytic cycle transactivators but is silenced during latency in hematopoietic progenitor cells (HPCs). Because the MIEP has poor activity in HPCs, it is unclear how viral transactivators are expressed during reactivation. It has been presumed that viral gene expression is reinitiated via de-repression of the MIEP. We demonstrate that immediate early transcripts arising from reactivation originate predominantly from alternative promoters within the canonical major immediate early locus. Disruption of these intronic promoters results in striking defects in re-expression of viral genes and viral genome replication in the THP-1 latency model. Furthermore, we show that these promoters are necessary for efficient reactivation in primary CD34 + HPCs. Our findings shift the paradigm for HCMV reactivation by demonstrating that promoter switching governs reactivation from viral latency in a context-specific manner.human cytomegalovirus | latency | reactivation R eactivation of latent human cytomegalovirus (HCMV) infection poses a life-threatening risk to immunocompromised individuals, such as stem cell or organ transplant recipients (1). While the HCMV replicative cycle has been studied extensively, our understanding of the mechanisms controlling the entry into and exit from latency is far from complete.During productive infection, the HCMV genome is transcribed in a temporal cascade composed of three kinetic classes of gene expression designated as immediate early (IE), early, and late (2). The IE proteins, in particular IE1-72 kilodalton (kDa) and IE2-86 kDa proteins, referred to as IE1 and IE2, play critical roles in initiating the HCMV lytic cycle by transactivating the expression of cellular and viral genes and suppressing the innate immune response (3). During latency, IE gene expression is repressed, resulting in diminished viral gene expression and the absence of productive replication (4). Signals that stimulate reactivation induce IE gene expression to allow reentry into the viral replicative cycle (5), and this de-repression of IE genes is considered a pivotal event controlling the switch between latent and reactivated states.The major immediate early promoter (MIEP) is a powerful promoter in cells permissive for lytic HCMV replication and drives high level expression of mRNAs encoding IE1 (UL123) and IE2 (UL122) (6-9). In cell types that support HCMV latency, however, such as CD34 + human progenitor cells (HPCs) and CD14 + monocytes, MIEP activity is diminished (10-12). Because re-expression of UL122 and UL123 is required for reactivation (13-15), it has been presumed that de-repression of the MIEP is critical to reinitiate the viral lytic cycle. However, the origin of UL123 and UL122 transcripts during HCMV reactivation has not been formally defined. ResultsRe-Expression of UL123 ...

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“…Our data identified EIF4G1 and CDK1 as novel downstream targets of PPARD in mouse IECs and human colorectal cancer organoids to promote colorectal cancer invasiveness. EIF4G1, an essential scaffold protein for assembling EIF4F protein complex to initiate mRNA translation (46), plays an important role in cancer progression (47). CDK1 regulates cellcycle-dependent (e.g., chromosome segregation, DNA repair; ref.…”

Section: Discussionmentioning

confidence: 99%

Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion

et al. 2019

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APC mutations activate aberrant b-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of b-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apc min mice has raised questions about the effects of PPARD on aberrant b-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (Apc D580 ) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed b-catenin activation via up-or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/ b-catenin signaling and suppressed organoid self-renewal.Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in Apc D580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer-invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARDmediated upregulation of other proinvasive pathways: connexin 43, PDGFRb, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness.Significance: These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis.

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Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

Cited by 57 publications

References 186 publications

Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

Alternative promoters drive human cytomegalovirus reactivation from latency

Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion

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