Exosomal miR-222-3p contributes to castration-resistant prostate cancer by activating mTOR signaling.

Despite the clinical benefits of androgen deprivation therapy, most patients with advanced androgen-dependent prostate cancer (ADPC) eventually relapse and progress to lethal androgen-independent prostate cancer (AIPC), also termed castration-resistant prostate cancer (CRPC). MiRNAs can be packaged into exosomes (Exos) and shuttled between cells. However, the roles and mechanisms of exosomal miRNAs involved in CRPC progression have not yet been fully elucidated. Here, we find that miR-222-3p is elevated in AIPC cells, which results in remarkable enhancement of cell proliferation, migration, and invasion ability. Furthermore, Exos released by AIPC cells can be uptaken by ADPC cells, thus acclimating ADPC cells to progressing to more aggressive cell types in vitro and in vivo through exosomal transfer of miR-222-3p. Mechanistically, Exos-miR-222-3p promoted ADPC cells transformed to AIPC-like cells, at least in part, by activating mTOR signaling through targeting MIDN. Our results show that AIPC cells secrete Exos containing miRNA cargo. These cargos can be transferred to ADPC cells through paracrine mechanisms that have a strong impact on cellular functional remodeling. The current work underscores the great therapeutic potential of targeting Exo miRNAs, either as a single agent or combined with androgen receptor pathway inhibitors for CRPC treatment.

Emerging proteins involved in castration­resistant prostate cancer via the AR­dependent and AR­independent pathways (Review).

Despite achieving optimal initial responses to androgen deprivation therapy, most patients with prostate cancer eventually progress to a poor prognosis state known as castration­resistant prostate cancer (CRPC). Currently, there is a notable absence of reliable early warning biomarkers and effective treatment strategies for these patients. Although androgen receptor (AR)­independent pathways have been discovered and acknowledged in recent years, the AR signaling pathway continues to play a pivotal role in the progression of CRPC. The present review focuses on newly identified proteins within human CRPC tissues. These proteins encompass both those involved in AR­dependent and AR­independent pathways. Specifically, the present review provides an in­depth summary and analysis of the emerging proteins within AR bypass pathways. Furthermore, the significance of these proteins as potential biomarkers and therapeutic targets for treating CRPC is discussed. Therefore, the present review offers valuable theoretical insights and clinical perspectives to comprehensively enhance the understanding of CRPC.

New insights into lipid metabolism and prostate cancer (Review).

Prostate cancer (PCa) is the most common malignant tumor of the male urological system and poses a severe threat to the survival of middle­aged and elderly males worldwide. The development and progression of PCa are affected by a variety of biological processes, including proliferation, apoptosis, migration, invasion and the maintenance of membrane homeostasis of PCa cells. The present review summarizes recent research advances in lipid (fatty acid, cholesterol and phospholipid) metabolic pathways in PCa. In the first section, the metabolism of fatty acids is highlighted, from formation to catabolism and associated proteins. Subsequently, the role of cholesterol in the pathogenesis and evolution of PCa is described in detail. Finally, the different types of phospholipids and their association with PCa progression is also discussed. In addition to the impact of key proteins of lipid metabolism on PCa growth, metastasis and drug resistance, the present review also summarizes the clinical value of fatty acids, cholesterol and phospholipids, as diagnostic and prognostic indicators and therapeutic targets in PCa.

Adefovir dipivoxil inhibits APL progression through degradation of the oncoprotein PML-RARA.

Acute promyelocytic leukemia (APL) is highly aggressive and is frequently associated with disseminated intravascular coagulation and high early death rates. Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with APL, there are limited treatments for APL patients with RA resistance. Here we report an atypical APL patient, with an APL-like disease that developed very slowly without anti-leukemia therapy for nearly 2 years. During that time, the patient only intermittently received anti-HBV drugs, i.e., the combination of adefovir dipivoxil (ADV) and entecavir (ETV), leading us to hypothesize that ADV and/or ETV could inhibit APL progression. Our results showed that anti-HBV drugs ADV and ETV both exhibited significantly inhibitory effects on APL cells, and ADV indicated a much greater cytotoxic effect than ETV on APL cells. We further found that ADV significantly promoted APL cell differentiation and apoptosis, thereby restraining the progression of APL. Most importantly, our study uncovered a novel mechanism of ADV prohibiting APL progression, which was mediated, at least in part, by inhibition of TRIB3 and degradation of the oncoprotein PML-RARA, therefore leading to APL cell differentiation and apoptosis. Taken together, our study demonstrated that ADV, an anti-HBV drug, had significantly inhibitory effects on APL, and provided a novel therapeutic strategy for APL patients with RA resistance.

Emerging Proteins in CRPC: Functional Roles and Clinical Implications.

Prostate cancer (PCa) is the most common cancer in men in the western world, but the lack of specific and sensitive markers often leads to overtreatment of prostate cancer which eventually develops into castration-resistant prostate cancer (CRPC). Novel protein markers for diagnosis and management of CRPC will be promising. In this review, we systematically summarize and discuss the expression pattern of emerging proteins in tissue, cell lines, and serum when castration-sensitive prostate cancer (CSPC) progresses to CRPC; focus on the proteins involved in CRPC growth, invasion, metastasis, metabolism, and immune microenvironment; summarize the current understanding of the regulatory mechanisms of emerging proteins in CSPC progressed to CRPC at the molecular level; and finally summarize the clinical applications of emerging proteins as diagnostic marker, prognostic marker, predictive marker, and therapeutic marker.

The MYH9 Cytoskeletal Protein Is a Novel Corepressor of Androgen Receptors.

In the progression of castration-resistant prostate cancer (CRPC), the androgen receptor (AR) that serves as a transcription factor becomes the most remarkable molecule. The transcriptional activity of AR is regulated by various coregulators. As a result, altered expression levels, an aberrant location or activities of coregulators promote the development of prostate cancer. We describe herein results showing that compared with androgen-dependent prostate cancer (ADPC) cells, AR nuclear translocation capability is enhanced in androgen-independent prostate cancer (AIPC) cells. To gain insight into whether AR coregulators are responsible for AR translocation capability, we performed coimmunoprecipitation (CO-IP) coupled with LC-MS/MS to screen 27 previously reported AR cofactors and 46 candidate AR cofactors. Furthermore, one candidate, myosin heavy chain 9 (MYH9), was identified and verified as a novel AR cofactor. Interestingly, the distribution of MYH9 was in both the cytoplasmic and nuclear compartments yet was enriched in the nucleus when AR was knocked down by AR shRNA, suggesting that the nuclear translocation of MYH9 was negatively regulated by AR. In addition, we found that blebbistatin, an inhibitor of MYH9, not only promoted AR nuclear translocation but also enhanced the expression of the AR target gene PSA, which indicates that MYH9 represses nuclear AR signaling. Taken together, our findings reveal that MYH9 appears to be a novel corepressor of AR plays a pivotal role in the progression of CRPC.

Emerging roles and mechanisms of microRNA­222­3p in human cancer (Review).

MicroRNAs (miRNAs/miRs) are a class of small non­coding RNAs that maintain the precise balance of various physiological processes through regulating the function of target mRNAs. Dysregulation of miRNAs is closely associated with various types of human cancer. miR­222­3p is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in tumor occurrence and progression. miR­222­3p in human biofluids, such as urine and plasma, may be a potential biomarker for the early diagnosis of tumors. In addition, miR­222­3p acts as a prognostic factor for the survival of patients with cancer. The present review first summarizes and discusses the role of miR­222­3p as a biomarker for diverse types of cancers, and then focuses on its essential roles in tumorigenesis, progression, metastasis and chemoresistance. Finally, the current understanding of the regulatory mechanisms of miR­222­3p at the molecular level are summarized. Overall, the current evidence highlights the crucial role of miR­222­3p in cancer diagnosis, prognosis and treatment.

SGK1 in Human Cancer: Emerging Roles and Mechanisms.

Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the "AGC" subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.