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Type Iγ phosphatidylinositol phosphate kinase regulates PD-L1 expression by activating NF-κB.

ABSTRACT: The programmed death-ligand 1 (PD-L1), by binding to PD-1 on the surface of immune cells, activates a major immune checkpoint pathway. Elevated expression of PD-L1 in tumor cells mediates tumor-induced T-cell exhaustion and immune suppression; therefore protect the survival of tumor cells. Although blockade of the PD-1/PD-L1 axis exhibits great potential in cancer treatment, mechanisms driving the up-regulation of PD-L1 in tumor cells remain not fully understood. Here we found that type Iγ phosphatidylinositol 4-phosphate (PtdIns(4)P) 5-kinase (PIPKIγ) is required for PD-L1 expression in triple negative breast cancer cells. Depletion of PIPKIγ inhibits both intrinsic and induced PD-L1 expression. Results from further analyses suggest that PIPKIγ promotes the transcription of the PD-L1 gene by activating the NF-κB pathway in these cells. These results demonstrate that PIPKIγ-dependent expression of PD-L1 is likely important for the progression of triple negative breast cancer.

SUBMITTER: Xue J

PROVIDER: S-EPMC5522076 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Nuclear Phosphatidylinositol-Phosphate Type I Kinase ?-Coupled Star-PAP Polyadenylation Regulates Cell Invasion.

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p70S6K1 (S6K1)-mediated Phosphorylation Regulates Phosphatidylinositol 4-Phosphate 5-Kinase Type I γ Degradation and Cell Invasion.

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Ubiquitylation of phosphatidylinositol 4-phosphate 5-kinase type I ? by HECTD1 regulates focal adhesion dynamics and cell migration.

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The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNAInduced Silencing of NF-κB-Inducing Kinase.

Project description:NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB-inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.

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Phosphatidylinositol 5 Phosphate 4-Kinase Regulates Plasma-Membrane PIP3 Turnover and Insulin Signaling.

Project description:Phosphatidylinositol 3,4,5-trisphosphate (PIP3) generation at the plasma membrane is a key event during activation of receptor tyrosine kinases such as the insulin receptor required for normal growth and metabolism. We report that in Drosophila, phosphatidylinositol 5 phosphate 4-kinase (PIP4K) is required to limit PIP3 levels during insulin receptor activation. Depletion of PIP4K increases the levels of PIP3 produced in response to insulin stimulation. We find that PIP4K function at the plasma membrane enhances class I phosphoinositide 3-kinase (PI3K) activity, although the catalytic ability of PIP4K to produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] at the plasma membrane is dispensable for this regulation. Animals lacking PIP4K show enhanced insulin signaling-dependent phenotypes and are resistant to the metabolic consequences of a high-sugar diet, highlighting the importance of PIP4K in normal metabolism and development. Thus, PIP4Ks are key regulators of receptor tyrosine kinase signaling with implications for growth factor-dependent processes including tumor growth, T cell activation, and metabolism.

| S-EPMC6591132 | biostudies-literature

A phosphatidylinositol phosphate kinase inhibits Ras activation and regulates chemorepulsion in Dictyostelium discoideum.

Project description:During developmental and immune responses, cells move towards or away from some signals. Although much is known about chemoattraction, chemorepulsion (the movement of cells away from a stimulus) remains poorly understood. Proliferating Dictyostelium discoideum cells secrete a chemorepellent protein called AprA. Examining existing knockout strains, we previously identified proteins required for AprA-induced chemorepulsion, and a genetic screen suggested that the enzyme phosphatidylinositol phosphate kinase A (PIPkinA, also known as Pik6) might also be needed for chemorepulsion. Here, we show that cells lacking PIPkinA are not repelled by AprA, and that this phenotype is rescued by expression of PIPkinA. To bias cell movement, AprA inhibits Ras activation at the side of the cell closest to the source of AprA, and we find that PIPkinA is required for AprA to inhibit Ras activation. PIPkinA decreases levels of phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3], and possibly because of these effects, potentiates phagocytosis and inhibits cell proliferation. Cells lacking PIPkinA show normal AprA binding, suggesting that PIPkinA regulates chemorepulsion at a step between the AprA receptor and AprA inhibition of Ras activation.

| S-EPMC10399982 | biostudies-literature

Targeting type Iγ phosphatidylinositol phosphate kinase overcomes oxaliplatin resistance in colorectal cancer

Project description:Rationale: Oxaliplatin is a widely used chemotherapy drug for advanced colorectal cancer (CRC) and its resistance is a major challenge for disease treatment. However, the molecular mechanism underlying oxaliplatin resistance remains largely elusive. Methods: An integrative analysis was performed to determine differentially expressed genes involved in oxaliplatin resistance. Loss- and gain-of-function studies were employed to investigate the roles of type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) on oxaliplatin resistance in CRC cells. Exosomes derived from CRC cell lines were assessed for PD-L1 level and the ability to promote oxaliplatin resistance. Quantitative real-time PCR, immunofluorescence, luciferase reporter assay, Western blotting and other techniques were conducted to decipher the molecular mechanism. Results: PIPKIγ was identified as a critical gene related to oxaliplatin resistance in CRC. Genetic manipulation studies revealed that PIPKIγ profoundly facilitated oxaliplatin resistance and affected the expression of DNA damage repair proteins. Mechanistically, PIPKIγ promoted the expression of the immune checkpoint molecule PD-L1 via activation of NF-κB signaling pathway. Genetic silencing of PD-L1 did not affect CRC cell proliferation but significantly sensitized CRC cells to oxaliplatin. Notably, PD-L1 was revealed to be encapsulated in the exosomes, and the addition of exosomal PD-L1 to sh-PD-L1 CRC cells restored oxaliplatin resistance. Pharmacological hijacking PIPKIγ-exosomal PD-L1 axis largely reduced oxaliplatin resistance in CRC cells. In vivo experiments showed that PD-L1 loss significantly blocked oxaliplatin resistance and the addition of PD-L1-enriched exosomes promoted tumor growth and reduced mouse survival time. Conclusion: Our findings reveal a previous unprecedented role of PIPKIγ in oxaliplatin resistance and provide a key mechanism of exosomal PD-L1 in CRC with potential therapeutics.

| S-EPMC9169372 | biostudies-literature

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