Limits...
Stress responses from the endoplasmic reticulum in cancer.

Kato H, Nishitoh H - Front Oncol (2015)

Bottom Line: The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling.More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR.In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki , Miyazaki , Japan.

ABSTRACT
The endoplasmic reticulum (ER) is a dynamic organelle that is essential for multiple cellular functions. During cellular stress conditions, including nutrient deprivation and dysregulation of protein synthesis, unfolded/misfolded proteins accumulate in the ER lumen, resulting in activation of the unfolded protein response (UPR). The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling. More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR. Interestingly, in cancer, these signaling pathways from the ER are often dysregulated, contributing to cancer cell metabolism. Thus, the signaling pathway from the ER may be a novel therapeutic target for various cancers. In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

No MeSH data available.


Related in: MedlinePlus

Role of the ER lipid signaling pathway. In the ER, glycerophospholipids and phosphatidylinositol are synthesized. Phosphatidylinositol is converted to highly phosphorylated forms. Conversion of PIP2 to PIP3 is promoted by PI3K, resulting in the regulation of cell proliferation, cell migration, and cell differentiation through the induction of PI3K-Akt-mTOR signaling. Sphingosine is also synthesized on the cytosolic surface of the ER through the de novo biosynthesis of ceramide. Both ceramide and sphingosine inhibit Akt activity via the activation of PKCδ and protein phosphatase 2A. Conversely, C1P and S1P antagonize the effects of ceramide and sphingosine and activate Akt, consequently contributing to cell survival, cell proliferation, and inflammation. Pro-oncogenesis-related lipids are indicated in red. Anti-oncogenesis-related lipids are indicated in blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4403295&req=5

Figure 3: Role of the ER lipid signaling pathway. In the ER, glycerophospholipids and phosphatidylinositol are synthesized. Phosphatidylinositol is converted to highly phosphorylated forms. Conversion of PIP2 to PIP3 is promoted by PI3K, resulting in the regulation of cell proliferation, cell migration, and cell differentiation through the induction of PI3K-Akt-mTOR signaling. Sphingosine is also synthesized on the cytosolic surface of the ER through the de novo biosynthesis of ceramide. Both ceramide and sphingosine inhibit Akt activity via the activation of PKCδ and protein phosphatase 2A. Conversely, C1P and S1P antagonize the effects of ceramide and sphingosine and activate Akt, consequently contributing to cell survival, cell proliferation, and inflammation. Pro-oncogenesis-related lipids are indicated in red. Anti-oncogenesis-related lipids are indicated in blue.

Mentions: The ER can be classically divided into two types, rough ER (rER) and smooth ER (sER), which have different functions and morphology (128). The rER is studded with ribosomes on the membrane surface; it forms a membranous sheet and plays an important role as a major site of protein synthesis. By contrast, the sER is ribosome-free and exists as a tubular or reticular network throughout the cytoplasm (128). A large number of reports have demonstrated that sER is the site of lipid biogenesis. Among various lipids and phospholipids, glycerophospholipids and sphingolipids are essential as major components of biological membranes, and they are also important as signaling molecules (129, 130). These signaling lipids play important roles in cellular processes such as cell proliferation, migration, metabolism, inflammation, and apoptosis (Figure 3). In addition, both rER and sER are composed mainly of glycerophospholipids [i.e., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol (PI), and phosphatidyleserine], and sphingolipids [i.e., sphingosine-1-phosphate (S1P) and sphingosine] (130). In these phospholipids, including both saturated and unsaturated fatty acids are usually disturbed in cancer cells (36–38). Recent studies have demonstrated that changing the balance between membrane phospholipid saturation and unsaturation activates UPR signaling (10, 12). Furthermore, alterations in fatty acid unsaturation in membranes are implicated in cancer (131). Based on these findings, it is believed that the UPR-regulated signaling lipids or their precursors may have important roles in tumorigenesis and in the maintenance of cancer cell metabolism.


Stress responses from the endoplasmic reticulum in cancer.

Kato H, Nishitoh H - Front Oncol (2015)

Role of the ER lipid signaling pathway. In the ER, glycerophospholipids and phosphatidylinositol are synthesized. Phosphatidylinositol is converted to highly phosphorylated forms. Conversion of PIP2 to PIP3 is promoted by PI3K, resulting in the regulation of cell proliferation, cell migration, and cell differentiation through the induction of PI3K-Akt-mTOR signaling. Sphingosine is also synthesized on the cytosolic surface of the ER through the de novo biosynthesis of ceramide. Both ceramide and sphingosine inhibit Akt activity via the activation of PKCδ and protein phosphatase 2A. Conversely, C1P and S1P antagonize the effects of ceramide and sphingosine and activate Akt, consequently contributing to cell survival, cell proliferation, and inflammation. Pro-oncogenesis-related lipids are indicated in red. Anti-oncogenesis-related lipids are indicated in blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403295&req=5

Figure 3: Role of the ER lipid signaling pathway. In the ER, glycerophospholipids and phosphatidylinositol are synthesized. Phosphatidylinositol is converted to highly phosphorylated forms. Conversion of PIP2 to PIP3 is promoted by PI3K, resulting in the regulation of cell proliferation, cell migration, and cell differentiation through the induction of PI3K-Akt-mTOR signaling. Sphingosine is also synthesized on the cytosolic surface of the ER through the de novo biosynthesis of ceramide. Both ceramide and sphingosine inhibit Akt activity via the activation of PKCδ and protein phosphatase 2A. Conversely, C1P and S1P antagonize the effects of ceramide and sphingosine and activate Akt, consequently contributing to cell survival, cell proliferation, and inflammation. Pro-oncogenesis-related lipids are indicated in red. Anti-oncogenesis-related lipids are indicated in blue.
Mentions: The ER can be classically divided into two types, rough ER (rER) and smooth ER (sER), which have different functions and morphology (128). The rER is studded with ribosomes on the membrane surface; it forms a membranous sheet and plays an important role as a major site of protein synthesis. By contrast, the sER is ribosome-free and exists as a tubular or reticular network throughout the cytoplasm (128). A large number of reports have demonstrated that sER is the site of lipid biogenesis. Among various lipids and phospholipids, glycerophospholipids and sphingolipids are essential as major components of biological membranes, and they are also important as signaling molecules (129, 130). These signaling lipids play important roles in cellular processes such as cell proliferation, migration, metabolism, inflammation, and apoptosis (Figure 3). In addition, both rER and sER are composed mainly of glycerophospholipids [i.e., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol (PI), and phosphatidyleserine], and sphingolipids [i.e., sphingosine-1-phosphate (S1P) and sphingosine] (130). In these phospholipids, including both saturated and unsaturated fatty acids are usually disturbed in cancer cells (36–38). Recent studies have demonstrated that changing the balance between membrane phospholipid saturation and unsaturation activates UPR signaling (10, 12). Furthermore, alterations in fatty acid unsaturation in membranes are implicated in cancer (131). Based on these findings, it is believed that the UPR-regulated signaling lipids or their precursors may have important roles in tumorigenesis and in the maintenance of cancer cell metabolism.

Bottom Line: The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling.More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR.In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki , Miyazaki , Japan.

ABSTRACT
The endoplasmic reticulum (ER) is a dynamic organelle that is essential for multiple cellular functions. During cellular stress conditions, including nutrient deprivation and dysregulation of protein synthesis, unfolded/misfolded proteins accumulate in the ER lumen, resulting in activation of the unfolded protein response (UPR). The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling. More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR. Interestingly, in cancer, these signaling pathways from the ER are often dysregulated, contributing to cancer cell metabolism. Thus, the signaling pathway from the ER may be a novel therapeutic target for various cancers. In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

No MeSH data available.


Related in: MedlinePlus