Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism

Abstract

Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

Keywords: androgen receptor; cancer metabolism; castration-resistant prostate cancer; long non-coding RNAs; micro RNAs; non-coding RNA.

Figure 1

Androgen receptor (AR) signaling and mechanisms of castration resistance. A number of microRNAs (miRNAs) that are either regulated by the AR (AR-targeted miRNAs) or directly bound to the AR mRNA 3′-untranslated region (AR-regulating miRNAs) invloved in the reactivation of AR signaling axis in castration-resistant prostate cancer (CRPC) are indicated and discussed in the text of the present article. T, testosterone; DHT, dihydrotestosterone; GF, growth factor; GFR, growth factor receptor; ↑, upregulation; ↓, downregulation.

Figure 2

The crucial role of miRNAs in coordinating vast prostate cancer (PC) metabolic processes. A number of miRNAs can reprogram PC metabolism by fine-tuning expressions of metabolic enzymes, and their regulators and signaling pathways. The steps affected by miRNAs are labelled by red circular arrows. Metabolites, metabolic enzymes, and transcription factors are indicated in black, blue, and green, respectively. All of the metabolic pathways are labeled with orange in bold. Black arrows indicate the direction of metabolite conversion, whereas green arrows point out the miRNAs or metabolic enzymes affected by the transcription factors. 3PG, 3-phosphoglyceric acid; α-KG, α-ketoglutarate; COX-2, cyclooxygenase-2; Δ1-pyyroline-5-carboxylate; FASN, fatty acid synthase; G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; GLS, glutaminase; GPX2, glutathione peroxidase-2; GS, glutamine synthetase; GSA, glutamic-γ-semialdehyde; HMGCR, 3-hydroxy-3-methylglutaryl CoA reductase; MnSOD, manganese superoxide dismutase; NRF2, nuclear factor erythroid-2-related factor 2; P5C, Δ1-pyyroline-5-carboxylate; PGD, 6-phosphogluconate dehydrogenase; PGE2, prostaglandin E2; POX/PRODH, proline oxidase/proline dehydrogenase; PPARA, peroxisome proliferator-activated receptor α; PPP, pentose phosphate pathway; PYCR, P5C reductase; SREBP-1, sterol regulatory element binding protein 1; SREBP-2, sterol regulatory element binding protein 2; TCA, tricarboxylic acid; TKT, transketolase; TrxR2, thioredoxin reductase-2.