Insulin-like growth factor-I induces chemoresistence to docetaxel by inhibiting miR-143 in human prostate cancer.

Xiao-Bing Niu,Hao-Ran Sun,Zeng-Jun Wang,Guang-Bo Fu,Bing-Hua Jiang,Lin Wang,Wei-Tao Liu,Xin Ge,Ling-Zhi Liu,Yi-Yang Wen

doi:10.18632/oncotarget.22362

Abstract

Elevated levels of insulin-like growth factor-I (IGF-I) are associated with carcinogenesis and cancer progression. However, the molecular mechanisms by which IGF-I promotes prostate cancer development remain to be elucidated. Docetaxel chemotherapy is an important therapeutic strategy in many types of human cancers including prostate cancer. In this study, we showed that IGF-I rendered PC-3 and DU145 cells more resistant to docetaxel treatment. IGF-I treatment decreased miR-143 expression, but increased the expression levels of IGF-I receptor (IGF-IR) and insulin receptor substrate 1 (IRS1), direct targets of miR-143. Overexpression of miR-143 abolished IGF-I-induced chemoresistance to docetaxel treatment, decreased expression levels of IGF-I, IRS1, and vascular endothelial growth factor (VEGF) in prostate cancer cell lines. Furthermore, docetaxel treatment significantly inhibited VEGF transcriptional activation, whereas IGF-I treatment induced VEGF transcriptional activation in a dose-dependent manner. Forced expression of IGF-IR and IRS1 cDNAs without the 3’ UTR regions restored miR-143-inhibited VEGF transcriptional activation. Finally, miR-143 inhibited tumor growth and made cells more sensitive to docetaxel treatment for decreasing tumor growth in vivo. Taken together, our data demonstrates that IGF-I induces docetaxel resistance and upregulates IGF-IR and IRS1 expression through miR-143 downregulation, whereas miR-143 acts as a tumor suppressor by targeting its targets IGF-IR and IRS1.

Highlights

Prostate cancer (PC) is the second leading cause of cancer death among men in the United States and the fourth most common tumor type worldwide [1, 2]
Docetaxel is used as a standard first-line drug for chemotherapy and is shown to have a survival advantage in metastatic castration-resistant PC with two to three months of median survival advantage and improved life quality when compared to mitoxantrone treatment [21, 22]
We found that insulin-like growth factor-I (IGF-I) increased resistance of PC-3 cells and DU145 cells to docetaxel treatment (Figure 1A and 1B), indicating that Insulin-like growth factor (IGF)-I axis may be involved in mediating docetaxel resistance in PC cells

Summary

Introduction

Prostate cancer (PC) is the second leading cause of cancer death among men in the United States and the fourth most common tumor type worldwide [1, 2]. Docetaxel is widely used as a first-line drug for chemotherapy, but cell resistance to docetaxel is a hindrance for PC treatment. MiRNAs are known to be involved in a variety of biological processes, including development, differentiation, apoptosis, and cell proliferation [7]. It has been demonstrated that miR-143 is a tumor suppressor in several types of cancer including prostate, breast and colorectal cancer [8,9,10]. By directly targeting protein-coding genes, miRNAs are capable to inhibit genes that are necessary for signaling pathways or drug-induced apoptosis to confer drug resistance. Downregulation of miR-205 and miR-31 promotes resistance by inhibiting chemotherapy-induced apoptosis in PC cells. It was reported that miR-148a attenuates paclitaxel resistance in PC3 cells by regulating MSK1 expression [18, 19]

Methods

Results

Conclusion