bims-stacyt 2022-08-28 papers

Cell Metab. 2022 Aug 19. pii: S1550-4131(22)00345-X. [Epub ahead of print]

Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα.

Dong Guo, Yingying Tong, Xiaoming Jiang, Ying Meng, Hongfei Jiang, Linyong Du, Qingang Wu, Shan Li, Shudi Luo, Min Li, Liwei Xiao, Haiyan He, Xuxiao He, Qiujing Yu, Jing Fang, Zhimin Lu.

High expression of PD-L1 in tumor cells contributes to tumor immune evasion. However, whether PD-L1 expression in tumor cells is regulated by the availability of nutrients is unknown. Here, we show that in human glioblastoma cells, high glucose promotes hexokinase (HK) 2 dissociation from mitochondria and its subsequent binding and phosphorylation of IκBα at T291. This leads to increased interaction between IκBα and μ-calpain protease and subsequent μ-calpain-mediated IκBα degradation and NF-κB activation-dependent transcriptional upregulation of PD-L1 expression. Expression of IκBα T291A in glioblastoma cells blocked high glucose-induced PD-L1 expression and promoted CD8+ T cell activation and infiltration into the tumor tissue, reducing brain tumor growth. Combined treatment with an HK inhibitor and an anti-PD-1 antibody eliminates tumor immune evasion and remarkably enhances the anti-tumor effect of immune checkpoint blockade. These findings elucidate a novel mechanism underlying the upregulation of PD-L1 expression mediated by aerobic glycolysis and underscore the roles of HK2 as a glucose sensor and a protein kinase in regulation of tumor immune evasion.

Keywords: HK2; IκBα; NF-κB; PD-L1; glycolysis; immune evasion; phosphorylation; protein kinase

DOI: https://doi.org/10.1016/j.cmet.2022.08.002

Cancers (Basel). 2022 Aug 18. pii: 4001. [Epub ahead of print]14(16):

The Immunomodulatory Role of Hypoxic Tumor-Derived Extracellular Vesicles.

Joel E J Beaumont, Nicky A Beelen, Lotte Wieten, Kasper M A Rouschop.

Tumor-associated immune cells frequently display tumor-supportive phenotypes. These phenotypes, induced by the tumor microenvironment (TME), are described for both the adaptive and the innate arms of the immune system. Furthermore, they occur at all stages of immune cell development, up to effector function. One major factor that contributes to the immunosuppressive nature of the TME is hypoxia. In addition to directly inhibiting immune cell function, hypoxia affects intercellular crosstalk between tumor cells and immune cells. Extracellular vesicles (EVs) play an important role in this intercellular crosstalk, and changes in both the number and content of hypoxic cancer-cell-derived EVs are linked to the transfer of hypoxia tolerance. Here, we review the current knowledge about the role of these hypoxic cancer-cell-derived EVs in immunosuppression. In addition, we provide an overview of hypoxia-induced factors (i.e., miRNA and proteins) in tumor-derived EVs, and their role in immunomodulation.

Keywords: cancer; extracellular vesicles; hypoxia; immunosuppression; immunotherapy; tumor microenvironment

DOI: https://doi.org/10.3390/cancers14164001

J Clin Endocrinol Metab. 2022 Aug 26. pii: dgac493. [Epub ahead of print]

Inflammatory cytokines rewire the proinsulin interaction in human islets.

Duc T Tran, Anita Pottekat, Kouta Lee, Megha Raghunathan, Salvatore Loguercio, Saiful A Mir, Adrienne W Paton, James C Paton, Peter Arvan, Randal J Kaufman, Pamela Itkin-Ansari.

CONTEXT: Aberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both Type I and Type II diabetes (T1D, T2D). Inflammatory cytokines are implicated in pancreatic islet stress and dysfunction in both forms of diabetes but the mechanisms remain unclear.OBJECTIVE: We sought to determine the effect of the diabetes associated cytokines on proinsulin folding, trafficking, secretion, and b-cell function.
DESIGN: Human islets were treated with interleukin-1β and interferon-γ for forty-eight hours, followed by analysis of IL6, nitrite, proinsulin and insulin release, RNAseq, and unbiased profiling of the proinsulin interactome by Affinity Purification-Mass Spectrometry (AP-MS).
RESULTS: Cytokine treatment induced secretion of IL6, nitrites, and insulin, as well as aberrant release of proinsulin. RNAseq showed that cytokines upregulated genes involved in ER stress and consistent with this, AP-MS revealed cytokine induced proinsulin binding to multiple ER chaperones and oxidoreductases. Moreover, increased binding to the chaperone BiP was required to maintain proper proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and T1D and T2D GWAS candidate proteins not previously known to interact with proinsulin (e.g., Ataxin-2). Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins and chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion.
CONCLUSION: Together, the data shed new light on mechanisms by which diabetes associated cytokines dysregulate β-cell function. For the first time we show that even short term exposure to an inflammatory environment reshapes proinsulin interactions with critical chaperones and regulators of the secretory pathway.

Keywords: Cytokines; Human Islets; Proinsulin; Protein Interactome; Type 1 Diabetes; Type 2 Diabetes

DOI: https://doi.org/10.1210/clinem/dgac493

Int J Mol Sci. 2022 Aug 12. pii: 9022. [Epub ahead of print]23(16):

A2B Adenosine Receptor Enhances Chemoresistance of Glioblastoma Stem-Like Cells under Hypoxia: New Insights into MRP3 Transporter Function.

José-Dellis Rocha, Daniel Uribe, Javiera Delgado, Ignacio Niechi, Sebastián Alarcón, José Ignacio Erices, Rómulo Melo, Rodrigo Fernández-Gajardo, Flavio Salazar-Onfray, Rody San Martín, Claudia Quezada Monrás.

Glioblastoma is the most common and aggressive primary brain tumor, characterized by its high chemoresistance and the presence of a cell subpopulation that persists under hypoxic niches, called glioblastoma stem-like cells (GSCs). The chemoresistance of GSCs is mediated in part by adenosine signaling and ABC transporters, which extrude drugs outside the cell, such as the multidrug resistance-associated proteins (MRPs) subfamily. Adenosine promotes MRP1-dependent chemoresistance under normoxia. However, adenosine/MRPs-dependent chemoresistance under hypoxia has not been studied until now. Transcript and protein levels were determined by RT-qPCR and Western blot, respectively. MRP extrusion capacity was determined by intracellular 5 (6)-Carboxyfluorescein diacetate (CFDA) accumulation. Cell viability was measured by MTS assays. Cell cycle and apoptosis were determined by flow cytometry. Here, we show for the first time that MRP3 expression is induced under hypoxia through the A2B adenosine receptor. Hypoxia enhances MRP-dependent extrusion capacity and the chemoresistance of GSCs. Meanwhile, MRP3 knockdown decreases GSC viability under hypoxia. Downregulation of the A2B receptor decreases MRP3 expression and chemosensibilizes GSCs treated with teniposide under hypoxia. These data suggest that hypoxia-dependent activation of A2B adenosine receptor promotes survival of GSCs through MRP3 induction.

Keywords: A2B; GSCs; MRP3; adenosine; chemoresistance; glioblastoma; hypoxia

DOI: https://doi.org/10.3390/ijms23169022

Biomedicines. 2022 Jul 29. pii: 1837. [Epub ahead of print]10(8):

GLUT3 Promotes Epithelial-Mesenchymal Transition via TGF-β/JNK/ATF2 Signaling Pathway in Colorectal Cancer Cells.

Moon-Young Song, Da-Young Lee, Sun-Mi Yun, Eun-Hee Kim.

Glucose transporter (GLUT) 3, a member of the GLUTs family, is involved in cellular glucose utilization and the first step in glycolysis. GLUT3 is highly expressed in colorectal cancer (CRC) and it leads to poor prognosis to CRC patient outcome. However, the molecular mechanisms of GLUT3 on the epithelial-mesenchymal transition (EMT) process in metastatic CRC is not yet clear. Here, we identified that activation of the c-Jun N-terminal kinase (JNK)/activating transcription factor-2 (ATF2) signaling pathway by transforming growth factor-β (TGF-β) promotes GLUT3-induced EMT in CRC cells. The regulation of GLUT3 expression was significantly associated with EMT-related markers such as E-cadherin, α- smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), vimentin and zinc finger E-box binding homeobox 1 (ZEB1). We also found that GLUT3 accelerated the invasive ability of CRC cells. Mechanistically, TGF-β induced the expression of GLUT3 through the phosphorylation of JNK/ATF2, one of the SMAD-independent pathways. TGF-β induced the expression of GLUT3 by increasing the phosphorylation of JNK, the nuclear translocation of the ATF2 transcription factor, and the binding of ATF2 to the promoter region of GLUT3, which increased EMT in CRC cells. Collectively, our results provide a new comprehensive mechanism that GLUT3 promotes EMT process through the TGF-β/JNK/ATF2 signaling pathway, which could be a potential target for the treatment of metastatic CRC.

Keywords: activating transcription factor-2; c-Jun N-terminal kinase; colorectal cancer; epithelial–mesenchymal transition; glucose transporter 3; transforming growth factor-β

DOI: https://doi.org/10.3390/biomedicines10081837