Downregulation of LRPPRC Induces Apoptosis in Prostate Cancer Cells Through the Mitochondria-Mediated Pathway

Address correspondence to: Nan Zhang; Department of Urology, , People's Hospital of Zhengzhou City; No. 33, Huanghe Road, Zhengzhou 450003, China, E-mail: [email protected]

Introduction

Prostate cancer (PCa) is the second most frequent tumor and the sixth leading cause of cancer-related death in men. PCa incidence has increased in the past few years. Despite recent therapeutic advances in the management of PCa, ∼15%-30% of patients with localized disease at diagnosis develop recurrence within 5-10 years, and most of these patients subsequently show poor therapeutic outcome.^1,2 Therefore, there is an urgent need to further understand the molecular mechanisms underlying the process responsible for the development of PCa.

PCa is a double-stage disease, which usually starts as a treatable and poorly aggressive neoplasm. For early-stage localized PCa, radical prostatectomy offers the best opportunity to eradicate the disease.³ After a variable time, PCa may evolve into an aggressive neoplasm, usually referred to as castration-resistant PCa,⁴ which is resistant to conventional treatments. It has become increasingly evident that molecular targets are available to treat castration-resistant PCa. For example, long noncoding RNA MALAT-1 was upregulated in human PCa tissue and cell lines, whereas MALAT-1 downregulation by small interfering RNA (siRNA) inhibited PCa cell growth, invasion and migration, and induced castration-resistant PCa cell cycle arrest in the G0/G1 phases. Furthermore, intratumor delivery of therapeutic siRNA targeting MALAT-1 elicited delayed tumor growth and reduced metastasis of PCa xenografts in castrated male nude mice, followed by the concomitant prolongation of the survival of tumor-bearing mice.⁵ Leucine-rich pentatricopeptide repeat motif-containing protein (LRPPRC) is an ∼130-kDa RNA-binding protein that is a target for the mitochondrial matrix.⁶ It is required for the expression of cyclooxygenase subunits that are encoded by mitochondrial DNA and transactivates nuclear DNAs. In addition, it coordinates mitochondrial translation and is necessary for the stabilization and polyadenylation of mitochondrial transcripts.⁷

Previous studies have demonstrated that LRPPRC is highly expressed in most cancers, such as hepatocellular cancer, lung adenocarcinoma, esophageal...