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Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells.

ABSTRACT: Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ in liver cancer cells. Imaging studies showed that secreted PKCδ interacted with EGFR-expressing cells in both autocrine and paracrine manners. Biochemical analysis revealed that PKCδ bound to the extracellular domain of EGFR. We further found that a part of the amino acid sequence on the C-terminal region of PKCδ was similar to the putative EGFR binding site of EGF. In this regard, the point mutant of PKCδ in the binding site lacked the ability to bind to the extracellular domain of EGFR. Upon an extracellular PKCδ-EGFR association, ERK1/2 activation, downstream of EGFR signaling, was apparently induced in liver cancer cells. This study indicates that extracellular PKCδ behaves as a growth factor and provides a molecular basis for extracellular PKCδ-targeting therapy for liver cancer.

SUBMITTER: Yamada K

PROVIDER: S-EPMC9277411 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells.

Yamada Kohji K Kizawa Ryusuke R Yoshida Ayano A Koizumi Rei R Motohashi Saya S Shimoyama Yuya Y Hannya Yoshito Y Yoshida Saishu S Oikawa Tsunekazu T Shimoda Masayuki M Yoshida Kiyotsugu K

Cancer science 20220512 7

Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ ...[more]

PMID: 35490382

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Project description:Chronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. The release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes ectopic mineralization of vessel walls. Caveolin-1 (CAV1), a structural protein in the plasma membrane, plays a major role in calcifying EV biogenesis in VSMCs. Epidermal growth factor receptor (EGFR) colocalizes with and influences the intracellular trafficking of CAV1. Using a diet-induced mouse model of CKD followed by a high-phosphate diet to promote vascular calcification, we assessed the potential of EGFR inhibition to prevent vascular calcification. Furthermore, we computationally analyzed 7,651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single-nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Mice with CKD developed widespread vascular calcification, associated with increased serum levels of EGFR. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice. Individuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. Given that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may represent an ideal target to prevent pathological vascular calcification in CKD.NEW & NOTEWORTHY Here, we investigate the potential of epidermal growth factor receptor (EGFR) inhibition to prevent vascular calcification, a leading indicator of and contributor to cardiovascular morbidity and mortality. EGFR interacts and affects the trafficking of the plasma membrane scaffolding protein caveolin-1. Previous studies reported a key role for caveolin-1 in the development of specialized extracellular vesicles that mediate vascular calcification; however, no role of EGFR has been reported. We demonstrated that EGFR inhibition modulates caveolin-1 trafficking and hinders calcifying extracellular vesicle formation, which prevents vascular calcification. Given that EGFR inhibitors are clinically approved for other indications, this may represent a novel therapeutic strategy for vascular calcification.

Project description:PurposeSubset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date.Patients and methodsA total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB).ResultsSixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi.ConclusionPatients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

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Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells.

Publications

Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells.

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