PKC-δ attenuates the cancer stem cell among squamous cell carcinoma cells through down-regulating p63

Zhang, Dongmei; Fu, Mingjing; Li, Lingyan; Ye, Huan; Song, Zhiqi; Piao, Yongjun

doi:10.1016/j.prp.2017.07.013

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…Interestingly, the up-regulation of KLF4 appeared more appreciable in confluent cells, the same culture condition in which the down-regulation of p63 was more evident: this simultaneous detection of p63 down-regulation and KLF4 induction mainly in confluent cells strongly suggests that they take place in the same step of the differentiation program, and possibly during the shift between the basal to the suprabasal layer. These observations, together with the recent evidence of a possible direct role of PKCδ in p63 down-regulation 54 , allowed us to speculate that the down-regulation of p63 could represent the molecular mechanism through which FGFR2b and its downstream PKCδ signaling could induce the up-regulation of KLF4 and consequently the onset of keratinocyte differentiation.…”

Section: Discussionmentioning

confidence: 72%

Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα

et al. 2018

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The tumor suppressor epithelial isoform of the fibroblast growth factor receptor 2 (FGFR2b) induces human keratinocyte early differentiation. Moreover, protein kinases C (PKCs) are known to regulate the differentiation program in several cellular contexts, including keratinocytes. Therefore, in this paper we propose to clarify if FGFR2b could play a role also in the late steps of keratinocyte differentiation and to assess if this receptor-induced process would sequentially involve PKCδ and PKCα isoforms. Immunofluorescence, biochemical, and molecular approaches, performed on 2D cultures or 3D organotypic rafts of human keratinocytes overexpressing FGFR2b by stable transduction, showed that receptor signaling induced the precocious onset and an accelerated progression of keratinocyte differentiation, indicating that FGFR2b is a crucial regulator of the entire program of keratinocyte differentiation. In addition, the use of specific inhibitors and gene silencing approaches through specific siRNA demonstrated that PKCδ controls the onset of FGFR2b-triggered differentiation, while PKCα plays a role restricted to the terminal stages of the process. Molecular analysis revealed that the two PKC isoforms sequentially act via induction of KLF4 and DLX3, two transcription factors linked by negative loops to p63, suggesting that p63 would represent the hub molecule at the crossroad of an intricate signaling network downstream FGFR2b, involving multiple PKC-induced transcription factors.

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Section: Discussionmentioning

confidence: 72%

Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα

et al. 2018

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“…LB100 has been leveraged in several clinical trials as a PP2A inhibitor owing to its efficacy and low toxicity [ 76 ]. In one study of pancreatic cancer, for example, LB100 was found to effectively radiosensitize pancreatic cancer cells without adversely affecting normal small intestinal cells [ 77 ]. LB100-mediated PP2A inhibition has also been shown to prevent radiation-induced Rad51 foci formation and homologous recombination repair, thereby causing sustained DNA damage in cells following radiation exposure [ 77 ].…”

Section: Introductionmentioning

confidence: 99%

“…In one study of pancreatic cancer, for example, LB100 was found to effectively radiosensitize pancreatic cancer cells without adversely affecting normal small intestinal cells [ 77 ]. LB100-mediated PP2A inhibition has also been shown to prevent radiation-induced Rad51 foci formation and homologous recombination repair, thereby causing sustained DNA damage in cells following radiation exposure [ 77 ]. The presence of undifferentiated stem-like tumor cells capable of undergoing self-renewal is thought to be one of the key mechanisms underlying tumor recurrence and therapeutic resistance.…”

Section: Introductionmentioning

confidence: 99%

PP2A and tumor radiotherapy

Xiao

et al. 2020

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Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that serves as a key regulator of cellular physiology in the context of apoptosis, mitosis, and DNA damage responses. Canonically, PP2A functions as a tumor suppressor gene. However, recent evidence suggests that inhibiting PP2A activity in tumor cells may represent a viable approach to enhancing tumor sensitivity to chemoradiotherapy as such inhibition can cause cells to enter a disordered mitotic state that renders them more susceptible to cell death. Indeed, there is evidence that inhibiting PP2A can slow tumor growth following radiotherapy in a range of cancer types including ovarian cancer, liver cancer, malignant glioma, pancreatic cancer, and nasopharyngeal carcinoma. In the present review, we discuss current understanding of the role of PP2A in tumor radiotherapy and the potential mechanisms whereby it may influence this process.

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“…Under the function of many cytokines, including IFN-α, PKC-δ has been shown to be activated by phosphorylation. Activated PKC-δ can inhibit cell proliferation and promote cell apoptosis [77,78]. This study showed that at 8 days and 11 days after B. microti infection in mice, both PKC-δ expression in the spleen and the phosphorylation modification level were downregulated.…”

Section: Growth and Development-related Proteinsmentioning

confidence: 72%

Protein regulation strategies of the mouse spleen in response to Babesia microti infection

et al. 2021

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Background Babesia is a protozoan parasite that infects red blood cells in some vertebrates. Some species of Babesia can induce zoonoses and cause considerable harm. As the largest immune organ in mammals, the spleen plays an important role in defending against Babesia infection. When infected with Babesia, the spleen is seriously injured but still actively initiates immunomodulatory responses. Methods To explore the molecular mechanisms underlying the immune regulation and self-repair of the spleen in response to infection, this study used data-independent acquisition (DIA) quantitative proteomics to analyse changes in expression levels of global proteins and in phosphorylation modification in spleen tissue after Babesia microti infection in mice. Results After mice were infected with B. microti, their spleens were seriously damaged. Using bioinformatics methods to analyse dynamic changes in a large number of proteins, we found that the spleen still initiated immune responses to combat the infection, with immune-related proteins playing an important role, including cathepsin D (CTSD), interferon-induced protein 44 (IFI44), interleukin-2 enhancer-binding factor 2 (ILF2), interleukin enhancer-binding factor 3 (ILF3) and signal transducer and activator of transcription 5A (STAT5A). In addition, some proteins related to iron metabolism were also involved in the repair of the spleen after B. microti infection, including serotransferrin, lactoferrin, transferrin receptor protein 1 (TfR1) and glutamate-cysteine ligase (GCL). At the same time, the expression and phosphorylation of proteins related to the growth and development of the spleen also changed, including protein kinase C-δ (PKC-δ), mitogen-activated protein kinase (MAPK) 3/1, growth factor receptor-bound protein 2 (Grb2) and P21-activated kinase 2 (PAK2). Conclusions Immune-related proteins, iron metabolism-related proteins and growth and development-related proteins play an important role in the regulation of spleen injury and maintenance of homeostasis. This study provides an important basis for the diagnosis and treatment of babesiosis.

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PKC-δ attenuates the cancer stem cell among squamous cell carcinoma cells through down-regulating p63

Cited by 8 publications

References 21 publications

Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα

Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα

PP2A and tumor radiotherapy

Protein regulation strategies of the mouse spleen in response to Babesia microti infection

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