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The therapeutic efficacy of metformin in prostate cancer (PCa) appears uncertain based on various clinical trials. Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation, which leads to drug resistance. However, the underlying mechanism is still unclear. In this study, we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation. Super-enhancers (SEs), crucial regulatory elements, have been shown to be associated with drug resistance in various cancers. Our analysis of SEs in metformin-resistant (MetR) PCa cells revealed a correlation with Prostaglandin Reductase 1 (PTGR1) expression, which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing. Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases, resulting in reduced sensitivity to metformin. Additionally, we identified key transcription factors that significantly increase PTGR1 expression, such as SRF and RUNX3, providing potential new targets to address metformin resistance in PCa. In conclusion, our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis, offering potential avenues to enhance metformins therapeutic efficacy in PCa.

Prostate cancer is a serious threat to the health of older adults worldwide. The quality of life and survival time of patients sharply decline once metastasis occurs. Thus, early screening for prostate cancer is very advanced in developed countries. The detection methods used include Prostate-specific antigen (PSA) detection and digital rectal examination. However, the lack of universal access to early screening in some developing countries has resulted in an increased number of patients presenting with metastatic prostate cancer. In addition, the treatment methods for metastatic and localized prostate cancer are considerably different. In many patients, early-stage prostate cancer cells often metastasize due to delayed observation, negative PSA results, and delay in treatment time. Therefore, the identification of patients who are prone to metastasis is important for future clinical studies. this review introduced a large number of predictive molecules related to prostate cancer metastasis. These molecules involve the mutation and regulation of tumor cell genes, changes in the tumor microenvironment, and the liquid biopsy. In next decade, PSMA PET/CT and liquid biopsy will be the excellent predicting tools, while 177 Lu- PSMA-RLT will be showed excellent anti-tumor efficacy in mPCa patients. [ABSTRACT FROM AUTHOR]

Myosin phosphatase target subunit 1 (MYPT1) is a subunit of myosin phosphatase that is capable of regulating smooth muscle contraction. MYPT1 has been reported to be involved in a wide variety of tumours, but its expression and biological functions in renal clear cell carcinoma (ccRCC) remain obscure. Herein, we analysed the relationship between patient clinicopathological characteristics and MYPT1 expression levels in ccRCC patients using a tissue microarray (TMA) and data retrieved from the TCGA‐KIRC dataset. MYPT1 was overexpressed or depleted using siRNA in ccRCC cells to assess the effects on migration and invasion in vitro and in vivo. Additionally, RNA‐sequencing and bioinformatics analysis were performed to investigate the precise mechanism. MYPT1 expression in ccRCC tissues was observed to be lower than that in nonmalignant tissues (P < 0.05). In addition, MYPT1 downregulation was closely linked to advanced pathological stage (P < 0.05), and poor OS (overall survival; P < 0.05). Functionally, increased expression of MYPT1 suppressed ccRCC migration and invasion in vitro, and inhibited tumour metastasis in vivo. In addition, MYPT1 overexpression exerted its suppressive effects via the MAPK8/N‐cadherin pathway in ccRCC. [ABSTRACT FROM AUTHOR]

Aim: To elucidates the mechanism that disulfiram/copper complex (DSF/Cu) treatment activates chloride channels and induces apoptosis in prostate cancer cells. Methods: Cellular membrane currents were measured by membrane clamp technique; western blot to detect protein expression; flow cytometry to detect apoptosis; immunofluorescence to detect target protein co‐localization, and further validated by a combination of protein‐protein interaction and mock protein molecular docking techniques. Results: DSF/Cu activated chloride channels and induced apoptosis in LNCaP (a type of androgen‐dependent prostate cancer cells) cells. The chloride currents activated by DSF/Cu were significantly reduced after knockdown of CLC3 with siRNA. In addition, DSF/Cu‐activated chloride currents were reduced to background current levels after perfusion with genistein, a highly specific tyrosine kinase inhibitor. Conversely, DSF/Cu failed to activate chloride currents in LNCaP cells after 30 minutes of pre‐incubation with genistein. When genistein was removed, and DSF/Cu was added, the activated currents were small and unstable, and gradually decreased. Immunofluorescence in LNCaP cells also showed co‐localization of the CLC3 protein with tyrosine kinase 2β (PTK2B). Conclusion: DSF/Cu can activate chloride channels and induce apoptosis in LNCaP cells with the involvement of tyrosine kinase. These results provide new insights into the target therapy of prostate cancer. [ABSTRACT FROM AUTHOR]

Chemotherapy has been proven to be an efficient strategy for the treatment of prostate cancer (PC). However, the insufficient cellular uptake of drugs is the biggest challenge for PC therapy. Therefore, in order to address the above concern, we developed tumor-targeted hyaluronic acid-silver nanoparticles (HA-Ag NPs), in which hyaluronic acid can specially bind with its receptor CD44 overexpressed on LNCaP cells. HA-Ag NPs have been used to load paclitaxel (PTX) to prepare functionalized silver nanoparticles (HA-Ag-PTX). The average particle size of HA-Ag-PTX was about 70 nm and kept under 120 nm for eight days. androgen-sensitive prostate cancer cells (LNCaP) cells show good uptake of HA-Ag-PTX, and HA-Ag-PTX enters LNCaP cells in a clathrin-mediated energy-dependent manner. HA-Ag-PTX exhibits an excellent pH response release of PTX under the acidic condition, which is beneficial to enhance the distribution of PTX in the tumor microenvironment. HA-Ag-PTX effectively suppresses the migration and proliferation of LNCaP cells probably by arresting the cellular cycle at G 0/ G 1 phase and enhancing the production of the reactive oxygen species. It is worth mentioning that HA-Ag-PTX exhibits greater anticancer activity in comparison with free PTX in the LNCaP cell model, indicating that HA-Ag NPs can effectively enhance the anticancer efficacy of PTX. As a whole, these findings suggest that HA-Ag-PTX has promising potential for PC therapy. Hyaluronic acid-modified silver nanoparticle loaded with paclitaxel (HA-Ag-PTX) was prepared in this study. Hyaluronic acid was used as cancer cells-targeted moiety. HA-Ag-PTX exhibited great ability to suppress the migration and proliferation of androgen-sensitive prostate cancer cells (LNCaP). Furthermore, HA-Ag-PTX could also induce the apoptosis of LNCaP. These findings suggest that HA-Ag-PTX has promising potential for prostate cancer therapy. [ABSTRACT FROM AUTHOR]

Tumor-adjacent normal (TAN) tissues, which constitute tumor microenvironment and are different from healthy tissues, provide critical information at molecular levels that can be used to differentiate aggressive tumors from indolent tumors. In this study, we analyzed 52 TAN samples from the Cancer Genome Atlas (TCGA) prostate cancer patients and developed a 10-gene prognostic model that can accurately predict biochemical recurrence-free survival based on the profiles of these genes in TAN tissues. The predictive ability was validated using TAN samples from an independent cohort. These 10 prognostic genes in tumor microenvironment are different from the prognostic genes detected in tumor tissues, indicating distinct progression-related mechanisms in two tissue types. Bioinformatics analysis showed that the prognostic genes in tumor microenvironment were significantly enriched by p53 signaling pathway, which may represent the crosstalk tunnels between tumor and its microenvironment and pathways involving cell-to-cell contact and paracrine/endocrine signaling. The insight acquired by this study has advanced our knowledge of the potential role of tumor microenvironment in prostate cancer progression. [ABSTRACT FROM AUTHOR]