scholarly journals Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma

2021 ◽  
Vol 22 (23) ◽  
pp. 13087
Author(s):  
Daniela Schulz ◽  
Martin Wetzel ◽  
Jonas Eichberger ◽  
Gerhard Piendl ◽  
Gero Brockhoff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Cellular Localization ◽  
Cell Cycle Progression ◽  
Checkpoint Inhibitors ◽  
Cycle Phase ◽  
Advanced Cancer Patients ◽  
Cycle Progression ◽  
Cellular Expression ◽  
Differentiation Status

The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.

scholarly journals A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Elliot C Woods ◽  
FuiBoon Kai ◽  
J Matthew Barnes ◽  
Kayvon Pedram ◽  
Michael W Pickup ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Cell Cycle Progression ◽  
Disseminated Tumor Cells ◽  
Metastatic Potential ◽  
Cancer Cell Growth ◽  
Cycle Progression ◽  
Growth And Survival ◽  
Syngeneic Mouse Model

Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression.

scholarly journals Murine Norovirus Replication Induces G0/G1Cell Cycle Arrest in Asynchronously Growing Cells

2015 ◽  
Vol 89 (11) ◽  
pp. 6057-6066 ◽  
Author(s):  
Colin Davies ◽  
Chris M. Brown ◽  
Dana Westphal ◽  
Joanna M. Ward ◽  
Vernon K. Ward
Keyword(s):  
Cell Cycle ◽  
Viral Replication ◽  
Host Cell ◽  
Virus Replication ◽  
Cell Cycle Progression ◽  
Cycle Phase ◽  
Murine Norovirus ◽  
Cycle Progression ◽  
Infected Cells ◽  
Favorable Conditions

ABSTRACTMany viruses replicate most efficiently in specific phases of the cell cycle, establishing or exploiting favorable conditions for viral replication, although little is known about the relationship between caliciviruses and the cell cycle. Microarray and Western blot analysis of murine norovirus 1 (MNV-1)-infected cells showed changes in cyclin transcript and protein levels indicative of a G1phase arrest. Cell cycle analysis confirmed that MNV-1 infection caused a prolonging of the G1phase and an accumulation of cells in the G0/G1phase. The accumulation in G0/G1phase was caused by a reduction in cell cycle progression through the G1/S restriction point, with MNV-1-infected cells released from a G1arrest showing reduced cell cycle progression compared to mock-infected cells. MNV-1 replication was compared in populations of cells synchronized into specific cell cycle phases and in asynchronously growing cells. Cells actively progressing through the G1phase had a 2-fold or higher increase in virus progeny and capsid protein expression over cells in other phases of the cell cycle or in unsynchronized populations. These findings suggest that MNV-1 infection leads to prolonging of the G1phase and a reduction in S phase entry in host cells, establishing favorable conditions for viral protein production and viral replication. There is limited information on the interactions between noroviruses and the cell cycle, and this observation of increased replication in the G1phase may be representative of other members of theCaliciviridae.IMPORTANCENoroviruses have proven recalcitrant to growth in cell culture, limiting our understanding of the interaction between these viruses and the infected cell. In this study, we used the cell-culturable MNV-1 to show that infection of murine macrophages affects the G1/S cell cycle phase transition, leading to an arrest in cell cycle progression and an accumulation of cells in the G0/G1phase. Furthermore, we show that MNV replication is enhanced in the G1phase compared to other stages of the cell cycle. Manipulating the cell cycle or adapting to cell cycle responses of the host cell is a mechanism to enhance virus replication. To the best of our knowledge, this is the first report of a norovirus interacting with the host cell cycle and exploiting the favorable conditions of the G0/G1phase for RNA virus replication.

scholarly journals Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation

2019 ◽  
Vol 12 (579) ◽  
pp. eaav1439 ◽  
Author(s):  
Olha M. Koval ◽  
Emily K. Nguyen ◽  
Velarchana Santhana ◽  
Trevor P. Fidler ◽  
Sara C. Sebag ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Cycle Phase ◽  
Wild Type ◽  
Mitochondrial Fragmentation ◽  
Cycle Progression ◽  
Regulatory Circuit

The role of the mitochondrial Ca2+uniporter (MCU) in physiologic cell proliferation remains to be defined. Here, we demonstrated that the MCU was required to match mitochondrial function to metabolic demands during the cell cycle. During the G1-S transition (the cycle phase with the highest mitochondrial ATP output), mitochondrial fusion, oxygen consumption, and Ca2+uptake increased in wild-type cells but not in cells lacking MCU. In proliferating wild-type control cells, the addition of the growth factors promoted the activation of the Ca2+/calmodulin-dependent kinase II (CaMKII) and the phosphorylation of the mitochondrial fission factor Drp1 at Ser616. The lack of the MCU was associated with baseline activation of CaMKII, mitochondrial fragmentation due to increased Drp1 phosphorylation, and impaired mitochondrial respiration and glycolysis. The mitochondrial fission/fusion ratio and proliferation in MCU-deficient cells recovered after MCU restoration or inhibition of mitochondrial fragmentation or of CaMKII in the cytosol. Our data highlight a key function for the MCU in mitochondrial adaptation to the metabolic demands during cell cycle progression. Cytosolic CaMKII and the MCU participate in a regulatory circuit, whereby mitochondrial Ca2+uptake affects cell proliferation through Drp1.

DNA damage inhibits proteolysis of the B-type cyclin Clb5 in S. cerevisiae

1997 ◽  
Vol 110 (15) ◽  
pp. 1813-1820
Author(s):  
D. Germain ◽  
J. Hendley ◽  
B. Futcher
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Tyrosine Phosphorylation ◽  
Cell Cycle Progression ◽  
Cycle Phase ◽  
Cycle Progression ◽  
Ubiquitin Pathway ◽  
Cyclin Dependent Kinases ◽  
Transition Points ◽  
Checkpoint Genes

Cell cycle progression is mediated by waves of specific cyclin dependent kinases (CDKs) in all eukaryotes. Cyclins are degraded by the ubiquitin pathway of proteolysis. The recent identification of several components of the cyclin proteolysis machinery has highlighted both the importance of proteolysis at multiple transition points in the cell cycle and the involvement of other substrates degraded by the same machinery. In this study, we have investigated the effects of DNA damage on the cyclin proteolytic machinery in Saccharomyces cerevisiae. We find that the half-life of the B-type cyclin Clb5 is markedly increased following DNA damage while that of G1 cyclins is not. This effect is independent of cell cycle phase. Clb5 turnover requires p34CDC28 activity. Stabilisation of Clb5 correlates with an increase in tyrosine phosphorylation of p34CDC28, but stabilisation does not require this tyrosine phosphorylation. The stabilisation is independent of the checkpoint genes Mec1 and Rad53. These observations establish a new link between the regulation of proteolysis and DNA damage.

scholarly journals DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells

Oncogene ◽  
2008 ◽  
Vol 27 (46) ◽  
pp. 6034-6043 ◽  
Author(s):  
E García-Aragoncillo ◽  
J Carrillo ◽  
E Lalli ◽  
N Agra ◽  
G Gómez-López ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Direct Target ◽  
Ewing’S Tumor

scholarly journals Effect of the Serum Inhibited Gene (Si1) on Autophagy and Apoptosis in MCF-7 Breast Cancer Cells

2017 ◽  
Vol 41 (6) ◽  
pp. 2268-2278 ◽  
Author(s):  
Yu Li ◽  
Yong Cui ◽  
Wenxue Wang ◽  
Mingxing Ma ◽  
Meizhang Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Western Blotting ◽  
Cell Cycle Progression ◽  
Hoechst 33258 ◽  
Cycle Progression ◽  
Important Relationship ◽  
M Phase ◽  
Inhibit Cell Proliferation ◽  
Mcf 7

Background/Aims: The serum inhibited gene (Si1) was named according to its inhibited expression in response to serum exposure. Si1 has an important relationship with tumors. Autophagy and apoptosis are two types of cell death. However, there are few studies regarding the association between Si1 and autophagy, or apoptosis in tumors. In this, we investigated the effect of Si1 on the proliferation and cell cycle progression of MCF-7 cells and its influence on autophagy and apoptosis in MCF-7 cells. Methods: To investigate these functions of Si1 in tumor cells, we firstly constructed a pEGFP-Si1 overexpression vector and a pSilencer-Si1 interference vector, and we subsequently tested the proliferation and cell cycle progression of MCF-7 cells using the MTT assay and flow cytometry, and we then detected autophagy by western blotting and MDC (Monodansylcadaverine) staining as well as apoptosis by western blotting and Hoechst 33258 staining. Results: We found that the Si1 gene can significantly inhibit the viability of MCF-7 cells and arrest the cell cycle at the G2/M phase. Si1 can induce autophagy through upregulation of LC3-II and Beclin1, it can induce apoptosis through cleavage of PARP in MCF-7 cells. Conclusion: Altogether, our study indicated that Si1 can inhibit cell proliferation of MCF-7, and also induces autophagy and apoptosis. This study firstly investigated the effect of Si1 on autophagy and apoptosis in MCF-7 cells. Moreover, it also improves the current understanding of the mechanisms related to the effect of Si1 on tumor cells and also provides a foundation for gene-targeted therapy.

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