Statins inhibit protein kinase D (PKD) activation in intestinal cells and prevent PKD1-induced growth of murine enteroids

Author:

Sinnett-Smith James12ORCID,Torres-Marquez M. Eugenia1,Chang Jen-Kuan1,Shimizu Yuki1,Hao Fang1,Martin Martin G.3,Rozengurt Enrique12ORCID

Affiliation:

1. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States

2. VA Greater Los Angeles Health Care System, Los Angeles, California, United States

3. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States

Abstract

We examined the impact of statins on protein kinase D (PKD) activation by G protein-coupled receptor (GPCR) agonists. Treatment of intestinal IEC-18 cells with cerivastatin inhibited PKD autophosphorylation at Ser916 induced by angiotensin II (ANG II) or vasopressin in a dose-dependent manner with half-maximal inhibition at 0.2 µM. Cerivastatin treatment inhibited PKD activation stimulated by these agonists for different times (5–60 min) and blunted HDAC5 phosphorylation, a substrate of PKD. Other lipophilic statins, including simvastatin, atorvastatin, and fluvastatin also prevented PKD activation in a dose-dependent manner. Using IEC-18 cell lines expressing PKD1 tagged with EGFP (enhanced green fluorescent protein), cerivastatin or simvastatin blocked GPCR-mediated PKD1-EGFP translocation to the plasma membrane and its subsequent nuclear accumulation. Similar results were obtained in IEC-18 cells expressing PKD3-EGFP. Mechanistically, statins inhibited agonist-dependent PKD activation rather than acting directly on PKD catalytic activity since exposure to cerivastatin or simvastatin did not impair PKD autophosphorylation or PKD1-EGFP membrane translocation in response to phorbol dibutyrate, which bypasses GPCRs and directly stimulates PKC and PKD. Furthermore, cerivastatin did not inhibit recombinant PKD activity determined via an in vitro kinase assay. Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds), and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells.

Funder

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of Allergy and Infectious Diseases

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

U.S. Department of Veterans Affairs

Hirshberg Foundation for Pancreatic Cancer Research

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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