An intercellular polyamine transfer via gap junctions regulates proliferation and response to stress in epithelial cells

Desforges, Bénédicte; Curmi, Patrick A.; Bounedjah, Ouissame; Nakib, Samir; Hamon, Loïc; Bandt, Jean‐Pascal De; Pastré, David

doi:10.1091/mbc.e12-10-0729

Cited by 20 publications

(18 citation statements)

References 66 publications

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“…). In line with this, we showed that quiescent cells deprived of polyamines resume cycling after the influx of polyamines from neighboring polyamine‐rich cells due to the presence of gap junction channels .…”

Section: What Are the Consequences And Putative Functions Of The Exchsupporting

confidence: 80%

“…Consistent with the theory on the exchange of polyamines, we recently reported that rat kidney epithelia cells deprived of polyamines can resume growing when they are connected to polyamine‐rich cells via gap junctions . Additionally, it was proposed that spermine can be exchanged from cell to cell to improve gap‐junction coupling between astrocytes at longer range than adjacent cells .…”

Section: Introductionsupporting

confidence: 58%

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Polyamine signal through gap junctions: A key regulator of proliferation and gap‐junction organization in mammalian tissues?

2016

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We propose that interaction rules derived from polyamine exchange in connected cells may explain the spatio-temporal organization of gap junctions observed during tissue regeneration and tumorigenesis. We also hypothesize that polyamine exchange can be considered as signal that allows cells to sense the proliferation status of their neighbors. Polyamines (putrescine, spermidine, and spermine) are indeed small aliphatic polycations that serve as fuels to sustain elevated proliferation rates of the order observed in cancer cells. Based on recent reports, we consider here that polyamines can be exchanged through gap junction channels between mammalian cells. Such intercellular exchange of polyamines has critical consequences on the local control of growth. In line with this hypothesis, the complex protein network that keeps polyamine levels finely tuned in mammalian cells can translate polyamine efflux or influx into integrated signals controlling transcription, translation, and cell communications.

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Section: What Are the Consequences And Putative Functions Of The Exchsupporting

confidence: 80%

Section: Introductionsupporting

confidence: 58%

Polyamine signal through gap junctions: A key regulator of proliferation and gap‐junction organization in mammalian tissues?

2016

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“…Such cells may then be more likely to form RNA granules during stress because they contain many polysomes. In agreement with this, when epithelial cells are forced to quiescence by contact inhibition, they have a low amount of mRNA and stress granule assembly is impaired in contrast with their proliferative counterparts (56). In metabolic-active neurons, disruption of the cell homeostasis may induce the dissociation of polysomes and the formation of RNA-rich aggregates containing RNA-binding proteins like TDP-43 or FUS, which may act as a critical step in neurodegenerative diseases (2,57–59).…”

Section: Discussionsupporting

confidence: 58%

Free mRNA in excess upon polysome dissociation is a scaffold for protein multimerization to form stress granules

et al. 2014

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The sequence of events leading to stress granule assembly in stressed cells remains elusive. We show here, using isotope labeling and ion microprobe, that proportionally more RNA than proteins are present in stress granules than in surrounding cytoplasm. We further demonstrate that the delivery of single strand polynucleotides, mRNA and ssDNA, to the cytoplasm can trigger stress granule assembly. On the other hand, increasing the cytoplasmic level of mRNA-binding proteins like YB-1 can directly prevent the aggregation of mRNA by forming isolated mRNPs, as evidenced by atomic force microscopy. Interestingly, we also discovered that enucleated cells do form stress granules, demonstrating that the translocation to the cytoplasm of nuclear prion-like RNA-binding proteins like TIA-1 is dispensable for stress granule assembly. The results lead to an alternative view on stress granule formation based on the following sequence of events: after the massive dissociation of polysomes during stress, mRNA-stabilizing proteins like YB-1 are outnumbered by the burst of nonpolysomal mRNA. mRNA freed of ribosomes thus becomes accessible to mRNA-binding aggregation-prone proteins or misfolded proteins, which induces stress granule formation. Within the frame of this model, the shuttling of nuclear mRNA-stabilizing proteins to the cytoplasm could dissociate stress granules or prevent their assembly.

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“…Combination therapies, which reduce polyamine levels, have been shown to slow tumor growth and enhance the immune response . Lastly, this area is ripe for drug discovery and future success in designing efficient polyamine‐targeting therapies could have broad applications in many human diseases, which rely on polyamines for growth and intercellular communication …”

Section: Discussionmentioning

confidence: 99%

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

Phanstiel

2017

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest major cancers, with a five year survival rate of less than 8%. With current therapies only giving rise to modest life extension, new approaches are desperately needed. Even though targeting polyamine metabolism is a proven anticancer strategy, there are no reports, which thoroughly survey the literature describing the role of polyamine biosynthesis and transport in PDAC. This review seeks to fill this void by describing what is currently known about polyamine metabolism in PDAC and identifies new targets and opportunities to treat this disease. Due to the pleiotropic effects that polyamines play in cells, this review covers diverse areas ranging from polyamine metabolism (biosynthesis, catabolism and transport), as well as the potential role of polyamines in desmoplasia, autophagy and immune privilege. Understanding these diverse roles provides the opportunity to design new therapies to treat this deadly cancer via polyamine depletion.

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An intercellular polyamine transfer via gap junctions regulates proliferation and response to stress in epithelial cells

Cited by 20 publications

References 66 publications

Polyamine signal through gap junctions: A key regulator of proliferation and gap‐junction organization in mammalian tissues?

Polyamine signal through gap junctions: A key regulator of proliferation and gap‐junction organization in mammalian tissues?

Free mRNA in excess upon polysome dissociation is a scaffold for protein multimerization to form stress granules

An overview of polyamine metabolism in pancreatic ductal adenocarcinoma

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