Mu‐KRAS attenuates Hippo signaling pathway through PKCι to sustain the growth of pancreatic cancer

Wang, Peipei; Zhang, Hongmei; Yang, Jinhe; Li, Zongxian; Wang, Yiren; Leng, Xiaohong; Ganapathy, Suthakar; Isakson, Pauline; Chen, Changyan; Zhu, Tingyao

doi:10.1002/jcp.28981

Cited by 10 publications

(7 citation statements)

References 43 publications

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“…Similar to RIPK2, PRKCI also has a higher expression in PC tissues than the normal, and a higher PRKCI expression predicts a poorer survival of PC patients. The oncogenic role of PRKCI-encoding protein PKC iota has been well established, recent studies in PC suggested that mutated KRAS can elevate and activate PKC iota to disable growth-inhibitory Hippo signaling and promote Yes-associated protein1 (YAP-1) translocation into nucleus, and thus maintain PC cells growth (Wang et al 2020 ). Also, PKC iota upregulates transcription factor specificity protein 1 to promote transactivation of YAP-1 and induce tumorigenesis (Yang et al 2021 ).…”

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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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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“…PKCι is upregulated and activated in pancreatic cancers with mutated KRAS, resulting in increased dephosphorylation and nuclear translocation of YAP1. These changes promote the growth of pancreatic cancer [ 248 ]. Inhibition of PKCι alone [ 249 ] or in combination with other inhibitors (e.g., specificity protein 1 (Sp1) inhibitor) [ 250 ] reduced cell growth and metastasis and induced apoptosis in pancreatic cancer cells.…”

Section: Pkc Isozymes As Prognostic Biomarkers or Therapeutic Targets...mentioning

confidence: 99%

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

Kawano

Inokuchi

Eto

et al. 2022

Cancers

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Protein kinase C (PKC) is a large family of calcium- and phospholipid-dependent serine/threonine kinases that consists of at least 11 isozymes. Based on their structural characteristics and mode of activation, the PKC family is classified into three subfamilies: conventional or classic (cPKCs; α, βI, βII, and γ), novel or non-classic (nPKCs; δ, ε, η, and θ), and atypical (aPKCs; ζ, ι, and λ) (PKCλ is the mouse homolog of PKCι) PKC isozymes. PKC isozymes play important roles in proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance in cancer cells. Several studies have shown a positive relationship between PKC isozymes and poor disease-free survival, poor survival following anticancer drug treatment, and increased recurrence. Furthermore, a higher level of PKC activation has been reported in cancer tissues compared to that in normal tissues. These data suggest that PKC isozymes represent potential diagnostic and prognostic biomarkers and therapeutic targets for cancer. This review summarizes the current knowledge and discusses the potential of PKC isozymes as biomarkers in the diagnosis, prognosis, and treatment of cancers.

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“…Furthermore, in breast cancer cells, knockout of POPX2 impaired anchorage-independent growth [60]. Inactivation of LATS by dephosphorylation in pancreatic cancer is caused by PKCiota cooperation with mutant KRas [61], both of which are up-regulated in PC and associated with disease progression [62].…”

Section: Post-translation Repression Of Lats1/2mentioning

confidence: 99%

Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Coffey

2021

Cancers

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Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

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Mu‐KRAS attenuates Hippo signaling pathway through PKCι to sustain the growth of pancreatic cancer

Cited by 10 publications

References 43 publications

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

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

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

Targeting the Hippo Pathway in Prostate Cancer: What’s New?

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