Induction of neuroendocrine differentiation in castration resistant prostate cancer cells by adipocyte differentiation-related protein (ADRP) delivered by exosomes

Highlights

• Lipogenesis-associated adiposome (PPARγ/ADRP) is critical for NED of CRPC.

• IL-6 or ADT induced NED is mediated by PPARγ/ADRP in PCa cells.

• ADRP protein can be delivered by exosomes to induce NED in a paracrine manner.

Abstract

Although overall mortality rate of prostate cancer (PCa) declines in recent years, castration-resistant prostate cancer (CRPC) remains incurable. Clinical evidence indicates that CRPC recurred from hormonal therapy exhibits neuroendocrine differentiated (NED) phenotypes, which could contribute to therapeutic resistance and poor survival. Understanding the onset of NED could lead us to develop new therapeutic strategies for CRPC. Although PCa is known as a lipid-enriched tumor, its role in CRPC development is not fully understood. In this study, we demonstrated that IL-6 or androgen deprivation therapy (ADT)-induced lipid accumulation is associated with NED phenotypes. IL-6 or ADT can induce NED in PCa cells via peroxisome proliferator-activated receptor γ (PPARγ, a major lipogenic transcription factor) and adipocyte differentiation-related protein (ADRP, a major component of adiposome). In addition, ADRP protein can be detected in exosomes released from these cells and these exosomes are capable of inducing NED of PCa cells in a paracrine fashion. Understanding the role of PPARγ/ADRP in NED could provide new target(s) for CRPC therapy.

Introduction

Prostate cancer (PCa) is the most common cancer among men in the United States [1]. The detection of early disease with local therapies has certainly improved the overall survival of PCa patients; however, the majority of mortality is caused by metastatic CRPC [2]. Current treatments such as androgen deprivation therapy (ADT) or chemotherapy for these patients are still unsatisfied. Obviously, characterizing cell features of CRPC could provide new strategies of eradicating this disease. Recent clinical findings of CRPC recurred from ADT [3], [4] indicate that some carcinoma cells exhibit neuroendocrine phenotypes with neuronal markers expression and neuronal factors secretion in an endocrine fashion [5], which is considered as neuroendocrine differentiation NED in PCa. NED can be classified into two categories in PCa: small cell carcinoma of prostate with neuroendocrine phenotypes (SCCP, accounts for 1% of the prostatic malignancies) and the recurrent carcinoma displaying NE features [6]. In advanced PCa, NED is frequently associated with highly proliferative area of tumor mass [7]; NED is known to increase chemo- or radio-resistance in PCa cells [8], [9]. Thus, understanding the onset of NED can certainly lead us to develop new therapeutic strategies for CRPC.

In CRPC, the mechanisms leading to NED is still poorly understood. Nevertheless, some factors such as cytokines (IL-1β, IL-6, IL-8), neuromediators (such as calcitonin, serotonin) and cAMP are able to induce NED [6]. Elevated serum IL-6 levels are associated with CRPC [10], [11], [12] and its receptor is also highly expressed in PCa tissues [13]. Although IL-6-induced NED is thought to be clinically relevant, the underlying mechanism is not clearly defined.

In PCa, elevated lipogenic enzymes, such as ATP citrate lyase (ACLY), fatty acid synthase (FASN) and stearoyl CoA desaturase 1 (SCD1), have been observed in clinical specimens [14]. Lipogenesis is mediated by a series of enzymes in converting Acetyl-CoA to fatty acids. These fatty acids are then stored in the form of lipids such as triacylglycerols (TGs). It is believed that the main energy source in growing tumor cell is de novo lipogenesis [15]. Indeed, these enzymes are able to promote the growth of PCa cells by either inhibiting apoptosis or promoting cell cycle [16], [17], [18]. In addition to lipogenic enzymes, adiposomes (also called lipid droplets or lipid bodies; the storage organelle for TGs) are commonly found in several cancers [19]. For example, colon and gastrointestinal cancer tissues with enlarged size and increased number of adiposomes [20], [21], however little is known in PCa.

Peroxisomal proliferator-activated receptor γ (PPARγ) is a master regulator for lipogenesis. To date, accumulating clinical evidence suggests PPARγ can function as a tumor promoter. PPARγ protein level is found significantly higher in advanced PCa than localized PCa or benign prostatic hyperplasia [22], [23]. Higher protein expression of PPARγ is also associated with shorter patient survival [24]. Recently, Ahmad and his colleagues demonstrated that PPARγ is critical for PCa metastases in Pten-null mice [25]. However, the relationship between adiposome accumulation and NED in CRPC cells remains unclear. In this study, we presented evidence that IL-6-elicited NED is mediated by PPARγ leading to elevated adipocyte differentiation-related protein (ADRP) associated with adiposome accumulation. Noticeably, ADRP can be released into exosome from PCa cells and induce NED of adjacent cells in a paracrine fashion. Taken together, this study provides new therapeutic targets in NED CRPC.