ArticleOncogene2014
Protein kinase Cα suppresses Kras-mediated lung tumor formation through activation of a p38 MAPK-TGFβ signaling axis.
Article in Oncogene, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 48 citations in OpenAlex.
- A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.Nature chemical biology · 2026Article
- PKCα regulates the secretion of PDL1-carrying small extracellular vesicles in a p53-dependent manner.Cell death & disease · 2025Article
- PKCActa pharmaceutica Sinica. B · 2024Article
- Article
- Circular RNA in Non-small Cell Lung Carcinoma: Identification of Targets and New Treatment Modalities.Cancer genomics & proteomics · 2023Review
- Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response.Biology · 2023Review
- KRAS mutation-induced EndMT of brain arteriovenous malformation is mediated through the TGF-β/BMP-SMAD4 pathway.Stroke and vascular neurology · 2023Article
- Notch signaling pathway: a comprehensive prognostic and gene expression profile analysis in breast cancer.BMC cancer · 2022Article
- Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer.Cancers · 2022Review
- PROTEIN KINASE C ALPHA IS A CENTRAL NODE FOR TUMORIGENIC TRANSCRIPTIONAL NETWORKS IN HUMAN PROSTATE CANCER.Cancer research communications · 2022Article
- PKC signal amplification suppresses non-small cell lung cancer growth by promoting p21 expression and phosphorylation.Heliyon · 2022Article
- Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity.Science signaling · 2022Review
- Thrombin Induces COX-2 and PGEMediators of inflammation · 2022Article
- The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis.Oncogene · 2021Article
- The complexities of PKCα signaling in cancer.Advances in biological regulation · 2021Review
- Exploring the five different genes associated with PKCα in bladder cancer based on gene expression microarray.Journal of cellular and molecular medicine · 2021Article
- PHLPPing the balance: restoration of protein kinase C in cancer.The Biochemical journal · 2021Review
- The KRAS/Lin28B axis maintains stemness of pancreatic cancer cells via the let-7i/TET3 pathway.Molecular oncology · 2021Article
- PKCCancer research · 2020Article
- Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Protein kinase C alpha (PKCα) can activate both pro- and anti-tumorigenic signaling depending upon cellular context. Here, we investigated the role of PKCα in lung tumorigenesis in vivo. Gene expression data sets revealed that primary human non-small lung cancers (NSCLC) express significantly decreased PKCα levels, indicating that loss of PKCα expression is a recurrent event in NSCLC. We evaluated the functional relevance of PKCα loss during lung tumorigenesis in three murine lung adenocarcinoma models (LSL-Kras, LA2-Kras and urethane exposure). Genetic deletion of PKCα resulted in a significant increase in lung tumor number, size, burden and grade, bypass of oncogene-induced senescence, progression from adenoma to carcinoma and a significant decrease in survival in vivo. The tumor promoting effect of PKCα loss was reflected in enhanced Kras-mediated expansion of bronchio-alveolar stem cells (BASCs), putative tumor-initiating cells, both in vitro and in vivo. LSL-Kras/Prkca(-/-) mice exhibited a decrease in phospho-p38 MAPK in BASCs in vitro and in tumors in vivo, and treatment of LSL-Kras BASCs with a p38 inhibitor resulted in increased colony size indistinguishable from that observed in LSL-Kras/Prkca(-/-) BASCs. In addition, LSL-Kras/Prkca(-/-) BASCs exhibited a modest but reproducible increase in TGFβ1 mRNA, and addition of exogenous TGFβ1 to LSL-Kras BASCs results in enhanced growth similar to untreated BASCs from LSL-Kras/Prkca(-/-) mice. Conversely, a TGFβR1 inhibitor reversed the effects of PKCα loss in LSL-Kras/Prkca(-/-) BASCs. Finally, we identified the inhibitors of DNA binding (Id) Id1-3 and the Wilm's Tumor 1 as potential downstream targets of PKCα-dependent tumor suppressor activity in vitro and in vivo. We conclude that PKCα suppresses tumor initiation and progression, at least in part, through a PKCα-p38MAPK-TGFβ signaling axis that regulates tumor cell proliferation and Kras-induced senescence. Our results provide the first direct evidence that PKCα exhibits tumor suppressor activity in the lung in vivo.
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