Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients. 

/pdf/targeting-autophagy-in-prostate-cancer-preclinical-and-1xlrhk1u.pdf

Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

Emerging roles for multifunctional ion channel auxiliary subunits in cancer.

The role of HOX transcript antisense RNA (HOTAIR) has been proven to be important in tumorigenesis. However, how this molecule promotes metastasis and invasion in PCa is still unclear. The relationship between HOTAIR and hepatocellular adhesion molecule (hepaCAM) in PCa was identified by immunohistochemistry, immunofluorescence, plasmid transfection, quantitative real-time PCR and immunoblotting. The regulatory effects of HOTAIR on hepaCAM and MAPK signalling and their key roles in PCa metastasis were investigated in vitro. The expression of HOTAIR was inversely correlated with hepaCAM in the blood and tissue of PCa patients. Here, hepaCAM was identified as a novel target gene of HOTAIR and was critical for the invasiveness of PCa. HOTAIR recruited PRC2 to the hepaCAM promoter, resulting in high levels of H3K27me3 and the absence of hepaCAM with an abnormally activated MAPK pathway. Both HOTAIR depletion and EZH2 inhibition could induce hepaCAM re-expression with inhibitory MAPK signalling and decrease the invasive and metastatic capabilities of PCa cells. This study demonstrates that HOTAIR promotes invasion and metastasis of PCa by decreasing the inhibitory effect of hepaCAM on MAPK signalling. Therefore, the HOTAIR/hepaCAM/MAPK axis may provide a new avenue towards therapeutic strategies and prognostic indicators for advanced prostate cancer.

Long noncoding RNA HOTAIR regulates the invasion and metastasis of prostate cancer by targeting hepaCAM

Prostate cancer stem-like cells (PCSCs) likely participate in tumor progression and recurrence and demonstrate resistance to chemotherapy The Notch pathway plays a role in the maintenance of the stemness in PCSCs This study aimed to investigate the efficacy of Notch signaling inhibition as an adjuvant to docetaxel (DOX) in PCSCs PCSCs derived from the PC-3 cell line were examined for Notch-1 expression The effect of Notch inhibition on response to DOX was evaluated in PCSCs in vitro and in murine models using a γ-secretase inhibitor (GSI), PF-03084014 Impacts on cell proliferation, apoptosis, cell cycle, and sphere formation were evaluated PC-3 PCSCs expressed elevated Notch-1 mRNA compared with PC-3 parental cells The combination of GSI with DOX promoted DOX-induced cell growth inhibition, apoptosis, cell cycle arrest, and sphere formation in PCSCs In nude mice bearing PC-3 PCSC-derived tumors, the combination of GSI and DOX reduced the tumor growth, which was associated with the decreased Notch-1 expression in tumor tissues These results reveal that inhibition of the Notch pathway enhances the anti-tumor effect of DOX in PC-3 PCSCs, and suggest that Notch inhibition may have clinical benefits in targeting PCSCs

/pdf/inhibition-of-notch-pathway-enhances-the-anti-tumor-effect-1471dxl5sy.pdf

Inhibition of Notch pathway enhances the anti-tumor effect of docetaxel in prostate cancer stem-like cells

Metabolic rewiring is a common feature of many cancer types, including prostate cancer (PCa). Alterations in master genes lead to mitochondrial metabolic rewiring and provide an appealing target to inhibit cancer progression and improve survival. Phospholipase C (PLC)e is a regulator of tumor generation and progression. However, its role in mitochondrial metabolism remains unclear. The GEO, The Cancer Genome Atlas, and the GTEx databases were used to determine Twist1 mRNA levels in tumors and their non-tumor counterparts. Fifty-five PCa and 48 benign prostatic hypertrophy tissue samples were tested for the presence of PLCe and Twist1 immunohistochemically. An association between PLCe and Twist1 was determined by Pearson’s correlation analysis. PLCe was knocked down with a lentiviral short hairpin RNA. Mitochondrial activity was assessed by measuring the oxygen consumption rate. Western blotting analyses were used to measure levels of PPARβ, Twist1, phosphorylated (p)-Twist1, p-MEK, p-ERK, p-P38, and p-c-Jun N-terminal kinase (JNK). Cells were treated with inhibitors of MEK, JNK, and P38 MAPK, and an agonist and inhibitor of peroxisome proliferator activated receptor (PPAR) β, to evaluate which signaling pathways were involved in PLCe-mediated Twist1 expression. The stability of Twist1 was determined after blocking protein synthesis with cycloheximide. Reporter assays utilized E-cadherin or N-cadherin luciferase reporters under depletion of PLCe or Twist1. Transwell assays assessed cell migration. Finally, a nude mouse tumor xenograft assay was conducted to verify the role of PLCe in tumor formation. Our findings revealed that the expression of PLCe was positively associated with Twist1 in clinical PCa samples. PLCe knockdown promoted mitochondrial oxidative metabolism in PCa cells. Mechanistically, PLCe increased phosphorylation of Twist1 and stabilized the Twist1 protein through MAPK signaling. The transcriptional activity of Twist1, and the Twist1-mediated epithelial-to-mesenchymal transition, cell migration, and transcription regulation, were suppressed by PLCe knockdown and by blocking PPARβ nuclear translocation. The tumor xenograft assay demonstrated that PLCe depletion diminished PCa cell tumorigenesis. These findings reveal an undiscovered physiological role for PLCe in the suppression of mitochondrial oxidative metabolism that has significant implications for understanding PCa occurrence and migration.

/pdf/plce-regulates-prostate-cancer-mitochondrial-oxidative-laqaojtean.pdf

PLCε regulates prostate cancer mitochondrial oxidative metabolism and migration via upregulation of Twist1.

Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the treatment of prostate cancer (PCa). The expression of hepatocyte cell adhesion molecule (HepaCAM), a novel tumor suppressor, is frequently downregulated or lost in PCa. Overactivated Notch signaling is involved in the development and progression of PCa, including CRPC. In this study, we found that the activities of Notch signaling were elevated, while HepaCAM expression was decreased in CRPC tissues compared with matched primary prostate cancer (PPC) tissues. In addition, HepaCAM negativity was found to be associated with a worse progression‑free survival (PFS). Furthermore, the overexpression of HepaCAM induced by transfection with a HepaCAM overexpression vector (Ad‑HepaCAM) exerted antitumor effects by decreasing the proliferation, and suppressing the invasion and migration of bicalutamide‑resistant (Bica‑R) cells and enzalutamide‑resistant (Enza‑R) cells. Importantly, we found that the antitumor effects of HepaCAM on the resistant cells were associated with the downregulation of Notch signaling. Moreover, we revealed that PF‑3084014 (a γ‑secretase inhibitor) re‑sensitized Enza‑R cells to enzalutamide, and sequential dual‑resistant (E+D‑R) cells to docetaxel. Additionally, the findings of this study demonstrated that the use of PF‑3084014 alone exerted potent antitumor effect on the resistant cells in vitro. On the whole, this study indicates that HepaCAM potentially represents a therapeutic target and PF‑3084014 may prove to a promising agent for use in the treatment of refractory PCa.

/pdf/hepacam-inhibits-the-malignant-behavior-of-castration-1vsy5vdvbb.pdf

HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro.

Phospholipase C-e (PLCe) is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made in understanding biological roles of PLCe, the relevant molecular mechanisms underlying its pro-tumor activity remain largely unclear. Here, we demonstrated that PLCe knockdown reduced cell metastasis, glucose consumption and lactate production in a manner that depended on hypoxia inducible factor 1α (HIF-1α) expression in prostate cancer cells. Interestingly, our findings showed that the expression levels of PLCe were positively associated with those of HIF-1α in clinical prostate carcinoma samples. Knockdown of PLCe impaired HIF-1α levels and transcriptional activity by regulating the extracellular-signal-regulated kinase pathway, and blocking HIF-1α nuclear translocation. Furthermore, PLCe could interact with the von Hippel-Lindau E3 ligase complex to modulate the stability of HIF-1α. Collectively, our findings demonstrate that PLCe could be a crucial positive regulator of HIF-1α, which would promote PLCe-enhanced tumorigenesis.

PLCε regulates metabolism and metastasis signaling via HIF-1α/MEK/ERK pathway in prostate cancer.

BACKGROUND Phospholipase Ce (PLCe), a member of the plc family, has been extensively studied to reveal its role in the regulation of different cell functions, but understanding of the underlying mechanisms remains limited. In the present study, we explored the effects of PLCe on PTEN (phosphatase and tensin homolog deleted on chromosome 10) in cell proliferation in prostate cancer cells. MATERIAL AND METHODS We assessed PLCe and PTEN expression in human benign prostate tissues compared to prostate cancer tissues by immunohistochemistry. Lentivirus-shPLCe (LV-shPLCe) was designed to silence PLCe expression in DU145 and PC3 cell lines, and the effectiveness was tested by qRT-PCR and Western blotting. MTT assay and colony formation assay were conducted to observe cell proliferation. Western blotting and immunofluorescence assays were used to detect changed PTEN expression in DU145. RESULTS We observed that PLCe expression was reduced in human benign prostate tissues compared to prostate cancer tissues, while PTEN expression showed the opposite trend. Silencing of the PLCe gene significantly inhibited cell proliferation in DU145 and PC3 cell lines. DU145 is a PTEN-expressing cell, while PC3 is PTEN-deficient. After infection by LV-shPLCe, we noticed that PTEN expression was up-regulated in DU145 cells but not in PC3 cells. Furthermore, we found that PLCe gene knockdown decreased P-AKT protein levels, but AKT protein levels were not affected. Immunofluorescence assays showed that PTEN expression had an intracellular distribution change in the DU145 cell line, and Western blot analysis showed that PTEN was obviously up-regulated in cell nucleus and cytoplasm. CONCLUSIONS PLCe is an oncogene, and knockdown of expression of PLCe inhibits PCa cells proliferation via the PTEN/AKT signaling pathway.

Knockdown of Phospholipase Cε (PLCε) Inhibits Cell Proliferation via Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN)/AKT Signaling Pathway in Human Prostate Cancer.

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HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro.

PLCε regulates prostate cancer mitochondrial oxidative metabolism and migration via upregulation of Twist1.

PLCε regulates metabolism and metastasis signaling via HIF-1α/MEK/ERK pathway in prostate cancer.

Knockdown of Phospholipase Cε (PLCε) Inhibits Cell Proliferation via Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN)/AKT Signaling Pathway in Human Prostate Cancer.