Statin induces apoptosis of human colon cancer cells and downregulation of insulin-like growth factor 1 receptor via proapoptotic ERK activation

Abstract

Abstract. Insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) signaling plays an important role in tumor progression in patients with certain gastrointestinal tract cancers. In addition to lowering cholesterol in serum, statins have pleiotropic effects, including anti-oxidative, anti-inflammatory or anti-neoplastic effects. Therefore, the present study investigated whether statins could induce the apoptosis of colon cancer cells and regulate the expression of IGF-1R and its associated signaling pathways in the present study. It was demonstrated that simvastatin and pravastatin suppressed cell proliferation and induced cell death in human HT-29 cells, but simvastatin was more potent than pravastatin. Simvastatin induced apoptosis in a concentration-dependent manner. In addition, simvastatin suppressed the expression of IGF-1R and inhibited the activity of phosphorylated-extracellular signal-regulated kinase (ERK)1/2 and phosphorylated-Akt activated by IGF-1. Simvastatin and IGF-1 each stimulated the activity of phosphorylated ERK1/2. However, simvastatin inhibited cell proliferation and IGF-1 stimulated cell proliferation. Mevalonic acid and PD98059 reversed the ERK activation and apoptosis induced by treatment with simvastatin. It was concluded that simvastatin induces the apoptosis of human colon cancer cells and inhibits IGF-1-induced ERK and Akt expression via the downregulation of IGF-1R expression and proapoptotic ERK activation. Simvastatin may be beneficial for the treatment of colon cancer. The present study suggested that statin may possess therapeutic potential for the treatment of colon cancer.

Inhibition of Fatty Acid Synthesis Induces Apoptosis of Human Pancreatic Cancer Cells

“…Murata et al found that Inhibition of FAS suppressed the proliferation of colon cancer cells in mice, which was followed by the induction of apoptosis (16). Moreover, several groups have suggested that agonists of peroxisome proliferator-activated receptor (PPAR) α, PPARγ and hydroxymethylglutaryl-CoA (HMG-CoA) reductase exerted an antitumor effect by reducing the levels of triacylglycerol and cholesterol (17)(18)(19)(20)(21). However, which aspect of lipid metabolism might be the best target for inhibition in order to provide the most effective induction of pancreatic cancer cell death is unclear.…”

Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors

“…Evidence gathered over the last years has prompted an emerging interest in exploring the putative role of statins in the development and progression of different endocrine-and non-endocrine-related tumors [11][12][13][14][15][16], particularly in view of recent meta-analysis analyzing several types of cancer, which revealed that the use of statins improves overall survival and cancer-specific survival [17]. However, to date, the possible antitumor actions of these compounds on PitNETs, as well as the direct effects of statins in normal pituitary cells, had not been reported.…”

“…However, besides their cholesterol-lowering effects, statins have been related with an ample range of pleiotropic effects including immunomodulatory effects triggering the major histocompatibility complex, improvement of endo-thelial function and vasculoprotective effects, alteration of bone metabolism, and so on, [9,10], which confer to statins the ability to affect numerous tissue functions acting through cholesterol-dependent and -independent mechanisms [10]. Importantly, some studies have also related the use of statins with antitumor properties in different endocrine-and non-endocrine-related tumors [11][12][13][14][15][16]. Indeed, a meta-analysis analyzing several types of cancer revealed that the use of statins seems to be beneficial for overall survival and cancer-specific survival [17].…”

The Effect of Statin Added to Systemic Anticancer Therapy: A Meta-Analysis of Randomized, Controlled Trials

“…FPP and GGPP are essential substrates for posttranslational modification of rat sarcoma viral oncogene homolog (RAS) and RAS homologue (RHO), which have important roles in growth, proliferation, migration, and survival [ 11 ]. Based on the role of statin on the posttranslational modifications of RAS and RHO, its potential antitumor effect has also been investigated [ 12 , 13 , 14 , 15 , 16 ]. Experimental studies have demonstrated that statins can inhibit tumor growth and induce apoptosis in a variety of cancer cell lines, including colorectal cancer (CRC) [ 12 ], pancreatic cancer (PC) [ 13 ], cholangiocarcinoma [ 14 ], breast cancer [ 15 ], and small-cell lung cancer (SCLC) [ 16 ].…”