Format

Send to

Choose Destination
Oncotarget. 2016 Apr 5;7(14):17905-19. doi: 10.18632/oncotarget.7560.

PKCδ regulates integrin αVβ3 expression and transformed growth of K-ras dependent lung cancer cells.

Author information

1
Program in Cancer Biology, The Graduate School, Aurora, CO, USA.
2
Matrix and Morphogenesis Section, NIDCR, NIH, Bethesda, MD, USA.
3
The Department of Craniofacial Biology, School of Dental Medicine, Aurora, CO, USA.
4
The Department of Medical Oncology, School of Medicine University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Abstract

We have previously shown that Protein Kinase C delta (PKCδ) functions as a tumor promoter in non-small cell lung cancer (NSCLC), specifically in the context of K-ras addiction. Here we define a novel PKCδ -> integrin αVβ3 ->Extracellular signal-Regulated Kinase (ERK) pathway that regulates the transformed growth of K-ras dependent NSCLC cells. To explore how PKCδ regulates tumorigenesis, we performed mRNA expression analysis in four KRAS mutant NSCLC cell lines that stably express scrambled shRNA or a PKCδ targeted shRNA. Analysis of PKCδ-dependent mRNA expression identified 3183 regulated genes, 210 of which were specifically regulated in K-ras dependent cells. Genes that regulate extracellular matrix and focal adhesion pathways were most highly represented in this later group. In particular, expression of the integrin pair, αVβ3, was specifically reduced in K-ras dependent cells with depletion of PKCδ, and correlated with reduced ERK activation and reduced transformed growth as assayed by clonogenic survival. Re-expression of PKCδ restored ITGAV and ITGB3 mRNA expression, ERK activation and transformed growth, and this could be blocked by pretreatment with a αVβ3 function-blocking antibody, demonstrating a requirement for integrin αVβ3 downstream of PKCδ. Similarly, expression of integrin αV restored ERK activation and transformed growth in PKCδ depleted cells, and this could also be inhibited by pretreatment with PD98059.Our studies demonstrate an essential role for αVβ3 and ERK signalingdownstream of PKCδ in regulating the survival of K-ras dependent NSCLC cells, and identify PKCδ as a novel therapeutic target for the subset of NSCLC patients with K-ras dependent tumors.

KEYWORDS:

KRAS; PKCδ; anchorage independent growth; integrins; lung cancer

PMID:
26918447
PMCID:
PMC4951259
DOI:
10.18632/oncotarget.7560
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center