Cholesterol-lowering drug pitavastatin targets lung cancer and angiogenesis via suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling

Abstract

Therapeutic agents that target both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy, particularly in lung cancer due to the critical roles of angiogenesis during lung cancer progression and metastasis. In this work, we showed that pitavastatin, a novel cholesterol-lowering drug, potently inhibited lung cancer cells and angiogenesis. This was achieved by the induction of apoptosis and inhibition of proliferation of lung cancer cells and human lung tumor-associated endothelial cell. Pitavastatin was not only effective to chemo-sensitive but also chemo-resistant lung cancer cells. This was also consistent with the finding that pitavastatin significantly enhanced cisplatin’s efficacy in lung cancer xenograft model without causing toxicity in mice. We further showed that pitavastatin inhibited lung tumor angiogenesis in vitro and in vivo through suppressing human lung tumor-associated endothelial cell migration and morphogenesis without affecting adhesion. Mechanistically, we showed that pitavastatin acted on lung cancer cells and human lung tumor-associated endothelial cell through suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling. Our work is the first to demonstrate the inhibitory effects of pitavastatin on Ras-mediated signaling. Our findings provide pre-clinical evidence to repurpose pitavastatin for the treatment of lung cancer.

The role of statins in lung cancer

“…Hu et al demonstrated that pitavastatin can inhibit LC cells and angiogenesis, which was achieved by the induction of apoptosis and inhibition of proliferation of LC cells and human lung tumor-associated endothelial cells. They also demonstrated that pitavastatin acted on LC cells and human lung tumor-associated endothelial cell by suppressing prenylation-dependent Ras/ Raf/MEK and PI3K/Akt/mTOR signaling [102].…”

Statins: a repurposed drug to fight cancer

“…Indeed, lower GGPP and FPP concentrations, leading to reduced RAS and Rho isoprenylation, signal transduction, and DNA synthesis, are important functional consequences of statins in the treatment of cancer [119,[158][159][160][161][162]. Inhibiting the farnesylation of these proteins restricts their activity and might hinder cancer cell proliferation [163,164]. Studies have shown that the inhibitory effect of simvastatin on the proliferation, migration and invasion of the gastric cancer cell lines MKN45 and MGC803 is due to a reduction in GGPP and RhoA activity mediated by inhibition of β-catenin and the Yes-associated protein (YAP) signaling pathways.…”

Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis

“…Lung cancer has the highest incidence worldwide and stands at second for its mortality rate ( Globocan, 2020 ). Non-small-cell lung carcinoma (NSCLC) shares 85% of all lung cancer and is insensitive toward cytotoxic chemotherapy ( Chen et al, 2014 ; Hu et al, 2020 ). In lung cancer, unusual overexpression or stimulation of Akt has been observed, linked with elevated cancer cell proliferation and survival ( Song et al, 2019 ).…”