PTHrP stimulates prostate cancer cell growth and upregulates aldo–keto reductase 1C3

Downs, Tracy M.; Burton, Douglas W.; Araiza, Flavio; Hastings, Randolph H.; Deftos, Leonard J.

doi:10.1016/j.canlet.2011.02.027

Cited by 37 publications

(28 citation statements)

References 28 publications

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“…The conditioned media from the picked cell colonies were evaluated for PTHrP expression by site-specific immunoassays and the PTHrP expressing stable DU145 cells were expanded [23], [26]. It has previously been shown that wild type and vector-transfected DU 145 exhibit a similar phenotype [27], [28]. Wild type parental DU 145 cells were thus used as a control for RT-qPCR and matrigel invasion experiments, however parallel experiments were performed with an empty vector-transfected control derivative.…”

Section: Methodsmentioning

confidence: 99%

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

et al. 2014

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Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP-overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer.

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Section: Methodsmentioning

confidence: 99%

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

et al. 2014

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“…Participation of AKR1C3 in cancer development is also well proven. Down-regulation of AKR1C3significantly decreases PCa and MCF7 breast cancer cell growth (Downs et al, 2011; Zhang et al, 2016b). Besides, silencing of AKR1C3 increases LCN2 expression and inhibits metastasis in cervical cancer (Wu et al, 2014).…”

Section: Catalytic-independent Biological Role and Cancermentioning

confidence: 99%

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

et al. 2017

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Aldo–keto reductases comprise of AKR1C1–AKR1C4, four enzymes that catalyze NADPH dependent reductions and have been implicated in biosynthesis, intermediary metabolism, and detoxification. Recent studies have provided evidences of strong correlation between the expression levels of these family members and the malignant transformation as well as the resistance to cancer therapy. Mechanistically, most studies focus on the catalytic-dependent function of AKR1C isoforms, like their impeccable roles in prostate cancer, breast cancer, and drug resistance due to the broad substrates specificity. However, accumulating clues showed that catalytic-independent functions also played critical roles in regulating biological events. This review summarizes the catalytic-dependent and -independent roles of AKR1Cs, as well as the small molecule inhibitors targeting these family members.

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“…The published data (Table 6) also suggest that in the transition from metastatic PC to CRPC the individual AKR1C genes may be induced by inflammatory and proliferative agents: such as interleukin IL-6 ( AKR1C2 [69]), activin A ( AKR1C3 [70]) and parathyroid hormone related protein (PTHrP) ( AKR1C1-AKR1C3 [71]). In this way induction of AKR1C genes may contribute to local androgen formation and prostate cancer relapse after androgen deprivation therapy.…”

Section: Expression Of Human Akr1 Genes In Diseasementioning

confidence: 99%

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

2014

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Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones, the biosynthesis of neurosteroids and bile acids, the metabolism of conjugated steroids, and synthetic therapeutic steroids. These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain. AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents, while AKR1D1 acts as the sole Δ4-3-ketosteroid-5β-reductase (steroid 5β-reductase) in humans. AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation, they also regulate the amount of neurosteroids that can modulate the activity of GABAA and NMDA receptors. As such they are involved in the pre-receptor regulation of nuclear and membrane bound receptors. Altered expression of individual AKR1C genes is related to development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.

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PTHrP stimulates prostate cancer cell growth and upregulates aldo–keto reductase 1C3

Cited by 37 publications

References 28 publications

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

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