PKCι regulates the expression of PDL1 through multiple pathways to modulate immune suppression of pancreatic cancer cells

Zhang, Hongmei; Zhu, Yue; Wang, Junli; Weng, Sijia; Zuo, Fengqiong; Li, Changlong; Zhu, Tingyao

doi:10.1016/j.cellsig.2021.110115

Cited by 6 publications

(9 citation statements)

References 55 publications

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“…Since we had previously pinpointed pdl1 as a STAT3 target gene in PDAC (Zhang et al 2021), here we used pdl1 as a reporter gene in our experiments to assess STAT3 transcriptional activity. Our data displayed that blocking STAT3 Y705 phosphorylation via PKCι shRNA or ATM suppressed PDL1 expression, whereas increasing pY705 STAT3 by PKCι overexpression enhanced PDL1 levels in PDAC cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study, we identified that PKCι promotes carcinogenesis and immunosuppressive TME in pancreatic tumors (Wang et al 2018, 2020; Yang et al 2021; Zhang et al 2021). Additionally, we found that PKCι affects the activity of signal transducer and activator of transcription 3 (STAT3) by inducing STAT3 Y705 phosphorylation in pancreatic ductal adenocarcinoma (PDAC) cells (Zhang et al 2021).…”

Section: Introductionmentioning

confidence: 97%

“…In a previous study, we identified that PKCι promotes carcinogenesis and immunosuppressive TME in pancreatic tumors (Wang et al 2018(Wang et al , 2020Yang et al 2021;Zhang et al 2021). Additionally, we found that PKCι affects the activity of signal transducer and activator of transcription 3 (STAT3) by inducing STAT3 Y705 phosphorylation in pancreatic ductal adenocarcinoma (PDAC) cells (Zhang et al 2021). STAT3 is a transcription factor (TF) regulating the expression of a plethora of target genes involved in various cancer-associated cellular processes, such as cell proliferation, stemness, metastasis, anti-apoptosis, angiogenesis, inflammation, and so on (Philips et al 2022).…”

Section: Introductionmentioning

confidence: 98%

“…Through regulating a variety of key signaling pathways that are involved in cell survival, proliferation, angiogenesis, epithelial‐mesenchymal transition (EMT), and metastasis, PKCι has been documented by multiple studies to be able to drive malignant transformation in diverse tumors, including non‐small‐cell lung carcinoma, colon cancer, hepatocellular carcinoma, stomach cancer, glioblastoma, cholangiocarcinoma, liver and pancreatic cancer (Fields et al 2007; Scotti et al 2010). Recent research by us and others has affirmed the roles of PKCι in promoting proliferation, restricting apoptosis, maintaining autophagy, and encouraging immunosuppression, therefore contributing to the initiation and progression of pancreatic cancer, as well as the development of drug resistance (Inman et al 2022; Kawano et al 2022; Wang et al 2018, 2020; Yang et al 2021; Zhang et al 2021). This establishes PKCι as a promising therapeutic target for pancreatic cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells

Wang,

Weng,

Zhu

et al. 2023

J. Cell Commun. Signal.

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An increasing number of studies have documented atypical protein kinase C isoform ι (PKCι) as an oncoprotein playing multifaceted roles in pancreatic carcinogenesis, including sustaining the transformed growth, prohibiting apoptosis, strengthening invasiveness, facilitating autophagy, as well as promoting the immunosuppressive tumor microenvironment of pancreatic tumors. In this study, we present novel evidence that PKCι overexpression increases STAT3 phosphorylation at the Y705 residue while decreasing STAT3 phosphorylation at the S727 residue in pancreatic cancer cells. We further demonstrate that STAT3 phosphorylation at Y705 and S727 residues is mutually antagonistic, and that STAT3 Y705 phosphorylation is positively related to the transcriptional activity of STAT3 in pancreatic cancer cells. Furthermore, we discover that PKCι inhibition attenuates STAT3 transcriptional activity via Y705 dephosphorylation, which appears to be resulted from enhanced phosphorylation of S727 in pancreatic cancer cells. Finally, we investigate and prove that by modulating the STAT3 activity, the PKCι inhibitor can synergistically enhance the antitumor effects of pharmacological STAT3 inhibitors or reverse the anti-apoptotic side effects incited by the MEK inhibitor, thereby posing as a prospective sensitizer in the treatment of pancreatic cancer cells.Junli Wang, Sijia Weng and Yue Zhu have contributed equally to this work.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells

Wang,

Weng,

Zhu

et al. 2023

J. Cell Commun. Signal.

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“…Also, PKC iota upregulates transcription factor specificity protein 1 to promote transactivation of YAP-1 and induce tumorigenesis (Yang et al 2021 ). In turn, the produced YAP-1 can be recruited by PKC iota to increase PD-L1 expression, resulting in immune evasion under the microenvironment of PC (Zhang et al 2021c ). These studies suggest a YAP-1 dependent manner in PKC iota driven carcinogenesis, growth and immune tolerance of PC.…”

Section: Discussionmentioning

confidence: 99%

Paired protein kinases PRKCI-RIPK2 promote pancreatic cancer growth and metastasis via enhancing NF-κB/JNK/ERK phosphorylation

Jiao

Ruan

Cheng

et al. 2023

Mol Med

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Background Protein kinases play a pivotal role in the malignant evolution of pancreatic cancer (PC) through mediating phosphorylation. Many kinase inhibitors have been developed and translated into clinical use, while the complex pathology of PC confounds their clinical efficacy and warrants the discovery of more effective therapeutic targets. Methods Here, we used the Gene Expression Omnibus (GEO) database and protein kinase datasets to map the PC-related protein kinase-encoding genes. Then, applying Gene Expression and Profiling Interactive Analysis (GEPIA), GEO and Human Protein Atlas, we evaluated gene correlation, gene expression at protein and mRNA levels, as well as survival significance. In addition, we performed protein kinase RIPK2 knockout and overexpression to observe effects of its expression on PC cell proliferation, migration and invasion in vitro, as well as cell apoptosis, reactive oxygen species (ROS) production and autophagy. We established PC subcutaneous xenograft and liver metastasis models to investigate the effects of RIPK2 knockout on PC growth and metastasis. Co-immunoprecipitation and immunofluorescence were utilized to explore the interaction between protein kinases RIPK2 and PRKCI. Polymerase chain reaction and immunoblotting were used to evaluate gene expression and protein phosphorylation level. Results We found fourteen kinases aberrantly expressed in human PC and nine kinases with prognosis significance. Among them, RIPK2 with both serine/threonine and tyrosine activities were validated to promote PC cells proliferation, migration and invasion. RIPK2 knockout could inhibit subcutaneous tumor growth and liver metastasis of PC. In addition, RIPK2 knockout suppressed autophagosome formation, increased ROS production and PC cell apoptosis. Importantly, another oncogenic kinase PRKCI could interact with RIPK2 to enhance the phosphorylation of downstream NF-κB, JNK and ERK. Conclusion Paired protein kinases PRKCI-RIPK2 with multiple phosphorylation activities represent a new pathological mechanism in PC and could provide potential targets for PC therapy.

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PKCα inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability

Yu,

Xiang,

Gao

et al. 2024

Acta Pharmaceutica Sinica B

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PKCι regulates the expression of PDL1 through multiple pathways to modulate immune suppression of pancreatic cancer cells

Cited by 6 publications

References 55 publications

PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells

PKCι induces differential phosphorylation of STAT3 to modify STAT3-related signaling pathways in pancreatic cancer cells

Paired protein kinases PRKCI-RIPK2 promote pancreatic cancer growth and metastasis via enhancing NF-κB/JNK/ERK phosphorylation

PKCα inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability

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