Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins

Abstract

HMG-CoA reductase, the proximal rate-limiting enzyme in the mevalonate pathway, is inhibited by statins. Beyond their cholesterol lowering impact, statins have pleiotropic effects and their use is linked to improved lung health. We have shown that mevalonate cascade inhibition induces apoptosis and autophagy in cultured human airway mesenchymal cells. Here, we show that simvastatin also induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in these cells. We tested whether coordination of ER stress, autophagy and apoptosis determines survival or demise of human lung mesenchymal cells exposed to statin. We observed that simvastatin exposure activates UPR (activated transcription factor 4, activated transcription factor 6 and IRE1α) and caspase-4 in primary human airway fibroblasts and smooth muscle cells. Exogenous mevalonate inhibited apoptosis, autophagy and UPR, but exogenous cholesterol was without impact, indicating that sterol intermediates are involved with mechanisms mediating statin effects. Caspase-4 inhibition decreased simvastatin-induced apoptosis, whereas inhibition of autophagy by ATG7 or ATG3 knockdown significantly increased cell death. In BAX(-/-)/BAK(-/-) murine embryonic fibroblasts, simvastatin-triggered apoptotic and UPR events were abrogated, but autophagy flux was increased leading to cell death via necrosis. Our data indicate that mevalonate cascade inhibition, likely associated with depletion of sterol intermediates, can lead to cell death via coordinated apoptosis, autophagy, and ER stress. The interplay between these pathways appears to be principally regulated by autophagy and Bcl-2-family pro-apoptotic proteins. These findings uncover multiple mechanisms of action of statins that could contribute to refining the use of such agent in treatment of lung disease.

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

“…This statin effect was not reversible with cholesterol co-treatment272851. It has been also shown that GGTI-298, but not FTI-277, can mimic the cytotoxic effects of statins, indicating that statins induce cell death by inactivating Rho/Rac GTPase activities52.…”

“…For the proteolytic activity of caspase-8 (IETD-ase), -3/-7 (DEVD-ase), -9 (LEHDase), Caspase-Glo ® -3/-7, -8, and -9 (Promega) were determined in luminometric assays according to the manufacturer’s instructions and our previous report5187. Briefly, cells were grown in 96-well plate (15,000 cells/well) and treated with simvastatin (10 μM, 36 h).…”

Innovations in asthma therapy: is there a role for inhaled statins?

“…neutrophils, eosinophils, lymphocytes, macrophages) [31,36,138], and reduce airway smooth muscle cell proliferation [43], oxidative stress [129], fibrosis [44], cytokine production [34,139], and mucus production [140]. The statins also induce apoptosis in cancerous or proliferative cells and airway mesenchymal cells [141], enhance macrophage efferocytosis [142], increase endothelial cell nitric oxide production [37], and improve cell barrier integrity [143]. …”

The role of statins as therapeutic agents in cancer

“…The product of HMG-CoA reductase activity, mevalonic acid, is a precursor of cholesterol and the isoprenoid intermediates farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Both FPP and GGPP play a central role in the process of prenylation, where FPP or GGPP are post-translationally added to a protein to facilitate cell membrane anchoring (Ghavami et al 2012(Ghavami et al , 2014Likus et al 2016). Isoprenoids are necessary for the post-translational modification of different proteins, such as GTPase proteins (Rho, Rac and Ras), which are important in many physiological processes.…”