The hexosamine biosynthetic pathway (HBP) is a glucose metabolism pathway that results in the synthesis of a nucleotide sugar UDP-GlcNAc, which is subsequently used for the post-translational ...modification (O-GlcNAcylation) of intracellular proteins that regulate nutrient sensing and stress response. The HBP is carried out by a series of enzymes, many of which have been extensively implicated in cancer pathophysiology. Increasing evidence suggests that elevated activation of the HBP may act as a cancer biomarker. Inhibition of HBP enzymes could suppress tumor cell growth, modulate the immune response, reduce resistance, and sensitize tumor cells to conventional cancer therapy. Therefore, targeting the HBP may serve as a novel strategy for treating cancer patients. Here, we review the current findings on the significance of HBP enzymes in various cancers and discuss future approaches for exploiting HBP inhibition for cancer treatment.
•The hexosamine biosynthetic pathway (HBP) is a side-branch pathway from glycolysis which generates a key molecule - UDP-GlcNAc.•A major downstream utilization of UDP-GlcNAc is for the post-translational modification - O-GlcNAcylation.•Global changes in protein O-GlcNAcylation are emerging as a general characteristic of cancer cells.•Many selective inhibitors against HBP enzymes are in the preclinical development stage and needed to be further optimized.
Background
Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ...ribosomal RNA (rRNA) transcription and a rate‐limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first‐in‐class Pol I inhibitor, BMH‐21, that targets cancer cells of multiple origins, and holds potential for clinical translation.
Methods
The effect of BMH‐21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models.
Results
We show that BMH‐21 inhibits Pol I transcription in metastatic, castration‐resistant, and enzalutamide treatment‐resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH‐21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide‐resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on‐target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13‐MYC|Hoxb13‐Cre|Ptenfl/fl (BMPC) mouse prostate cancer model.
Conclusion
Taken together, BMH‐21 is a novel promising molecule for the treatment of castration‐resistant prostate cancer.
The discovery of small, "cave-like" invaginations at the plasma membrane, called caveola, has opened up a new and exciting research area in health and diseases revolving around this cellular ...ultrastructure. Caveolae are rich in cholesterol and orchestrate cellular signaling events. Within caveola, the caveola-associated proteins, caveolins and cavins, are critical components for the formation of these lipid rafts, their dynamics, and cellular pathophysiology. Their alterations underlie human diseases such as lipodystrophy, muscular dystrophy, cardiovascular disease, and diabetes. The expression of caveolins and cavins is modulated in tumors and in tumor stroma, and their alterations are connected with cancer progression and treatment resistance. To date, although substantial breakthroughs in cancer drug development have been made, drug resistance remains a problem leading to treatment failures and challenging translation and bench-to-bedside research. Here, we summarize the current progress in understanding cancer drug resistance in the context of caveola-associated molecules and tumor stroma and discuss how we can potentially design therapeutic avenues to target these molecules in order to overcome treatment resistance.
Background
Resistance to androgen deprivation therapies is a major driver of mortality in advanced prostate cancer. Therefore, there is a need to develop new preclinical models that allow the ...investigation of resistance mechanisms and the assessment of drugs for the treatment of castration‐resistant prostate cancer.
Methods
We generated two novel cell line models (LAPC4‐CR and VCaP‐CR) which were derived by passaging LAPC4 and VCaP cells in vivo and in vitro under castrate conditions. We performed detailed transcriptomic (RNA‐seq) and proteomic analyses (SWATH‐MS) to delineate expression differences between castration‐sensitive and castration‐resistant cell lines. Furthermore, we characterized the in vivo and in vitro growth characteristics of these novel cell line models.
Results
The two cell line derivatives LAPC4‐CR and VCaP‐CR showed castration‐resistant growth in vitro and in vivo which was only minimally inhibited by AR antagonists, enzalutamide, and bicalutamide. High‐dose androgen treatment resulted in significant growth arrest of VCaP‐CR but not in LAPC4‐CR cells. Both cell lines maintained AR expression, but exhibited distinct expression changes on the mRNA and protein level. Integrated analyses including data from LNCaP and the previously described castration‐resistant LNCaP‐abl cells revealed an expression signature of castration resistance.
Conclusions
The two novel cell line models LAPC4‐CR and VCaP‐CR and their comprehensive characterization on the RNA and protein level represent important resources to study the molecular mechanisms of castration resistance.
Lipid uptake occurs through caveolae, plasma membrane invaginations formed by caveolins (CAV) and caveolae-associated protein 1 (CAVIN1). Genetic alterations of
and
modify lipid metabolism and ...underpin lipodystrophy syndromes. Lipids contribute to tumorigenesis by providing fuel to cancer metabolism and supporting growth and signaling. Tumor stroma promotes tumor proliferation, invasion, and metastasis, but how stromal lipids influence these processes remain to be defined. Here, we show that stromal CAVIN1 regulates lipid abundance in the prostate cancer microenvironment and suppresses metastasis. We show that depletion of CAVIN1 in prostate stromal cells markedly reduces their lipid droplet accumulation and increases inflammation. Stromal cells lacking CAVIN1 enhance prostate cancer cell migration and invasion. Remarkably, they increase lipid uptake and M2 inflammatory macrophage infiltration in the primary tumors and metastasis to distant sites. Our data support the concept that stromal cells contribute to prostate cancer aggressiveness by modulating lipid content and inflammation in the tumor microenvironment. IMPLICATIONS: This study showed that stromal CAVIN1 suppresses prostate cancer metastasis by modulating tumor microenvironment, lipid content, and inflammatory response.
RNA Polymerase I (Pol I) synthesizes rRNA, which is the first and rate-limiting step in ribosome biogenesis. Factors governing the stability of the polymerase complex are not known. Previous studies ...characterizing Pol I inhibitor BMH-21 revealed a transcriptional stress-dependent pathway for degradation of the largest subunit of Pol I, RPA194. To identify the E3 ligase(s) involved, we conducted a cell-based RNAi screen for ubiquitin pathway genes. We establish Skp–Cullin–F-box protein complex F-box protein FBXL14 as an E3 ligase for RPA194. We show that FBXL14 binds to RPA194 and mediates RPA194 ubiquitination and degradation in cancer cells treated with BMH-21. Mutation analysis in yeast identified lysines 1150, 1153, and 1156 on Rpa190 relevant for the protein degradation. These results reveal the regulated turnover of Pol I, showing that the stability of the catalytic subunit is controlled by the F-box protein FBXL14 in response to transcription stress.
Polymerase-1 and release transcript factor (PTRF) was initially reported to be involved in the termination of the transcription process. More recently, it has been implicated in the formation of ...caveolae, cave-like structures in the plasma membrane. The effects of PTRF related to caveolae suggest that this protein may play important roles in health and disease. PTRF is highly expressed in various cells, including adipocytes, osteoblasts and muscle (cardiac, skeletal and smooth) cells. The role of PTRF in prostate cancer has been recently reviewed but there is growing evidence that PTRF is involved in other physiological processes such as cell repair and the regulation of glucose and lipid metabolism and, furthermore, altered expression of PTRF may be associated with disease. This review discusses the emerging role of PTRF in health and disease.
Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is ...critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.
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•AR inhibition reduces DRP1 S616 phosphorylation, causing mitochondrial elongation•MYC regulates AR inhibition-induced reduction in glycolysis and glutaminolysis•MYC regulates AR inhibition-induced reliance on mitochondrial oxidative metabolism
Resistance to androgen receptor (AR) inhibition is a major cause of prostate cancer-associated lethality. Crowell et al. comprehensively characterize the metabolic response to AR inhibition using transcriptomics, metabolomics, and bioenergetics. MYC activity and DRP1 phosphorylation regulate treatment-induced metabolic phenotypes and vulnerabilities, including sensitivity to complex I inhibition.
Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought ...to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.
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