Dataset Information

Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.

ABSTRACT: The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC.The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts.Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha.Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.

SUBMITTER: Li Y

PROVIDER: S-EPMC3196615 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.

Li Yirong Y Ligr Martin M McCarron James P JP Daniels Garrett G Zhang David D Zhao Xin X Ye Fei F Wang Jinhua J Liu Xiaomei X Osman Iman I Mencher Simon K SK Lepor Hebert H Wang Long G LG Ferrari Anna A Lee Peng P

Clinical cancer research : an official journal of the American Association for Cancer Research 20110523 13

<h4>Purpose</h4>The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC.<h4>Experimental design</h4>The growth kinetics and invasion ab ...[more]

PMID: 21606178

Similar Datasets

Project description:The composition of the prostate microbiome may influence the fate of the cells that may be relevant to prostate morbidity. Several independent studies have reported the presence of the bacterium Propionibacterium acnes in diseased human prostate tissue. It is unclear if the bacterium is an infectious agent, part of a normal prostate microbiota or if it is derived from the skin and accidentally introduced, for instance during a prostate biopsy. Previous research with prostate cell culture and animal models has revealed the capability of P. acnes to establish a low-grade chronic inflammation. However, the fate of primary prostate cells exposed to P. acnes has not been investigated in molecular detail. Here, we investigated the impact of P. acnes on human primary prostate epithelial cells (PrEC). An initial analysis of the host cell response by microarray technology confirmed the inflammation-inducing capability of P. acnes but also showed the deregulation of genes involved in cell cycle, and more specifically in kinetochore and centromere functionality. In particular, we could show and confirm by qPCR that only viable P. acnes downregulated a master regulator of cell cycle progression, FOXM1, as well as its target genes. It was further shown by flow cytometry that P. acnes was indeed able to alter the cell cycle by increasing the number of PrEC cells in S-phase. In search for a molecular explanation we tested the hypothesis that a P.acnes produced berninamycin A-like thiopeptide, that is a structurally closely related to the known FOXM1 inhibitor siomycin A, is responsible for the effect on FOXM1 and the cell cycle. A knock-out mutant in P. acnes was created that lacked the gene encoding the berninamycin A peptide precursor; this mutant was unable to downregulate FOXM1, suggesting that a berninamycin A-like thiopeptide induces cell cycle alterations in PrEC cells. Interestingly, the gene cluster encoding this thiopeptide is restricted to a subtype of P. acnes that is relatively rare on human skin, but more often found in prostate tissue.

Project description:Background and aim: Understanding the molecular biological mechanisms underlying laryngeal squamous cell carcinoma (LSCC) invasion and metastasis is crucial for diagnosis, treatment, and prognosis. We aimed to examine the expression of the tumor suppressor microRNA-204-5p (miR-204-5p) and its target gene, forkhead box C1 (FOXC1), in human LSCC and explore their roles in the malignant behaviors of LSCC Hep-2 and TU-177 cells. Methods: The regulatory effects of miR-204-5p on the 3' untranslated region of FOXC1 predicted by bioinformatics were tested by dual-luciferase reporter assay. Quantitative RT-PCR was used to detect mRNA expression in 43 fresh samples of LSCC and corresponding adjacent normal mucosa (ANM). FOXC1 protein expression was examined by immunohistochemistry. miR-204-5p mimics and FOXC1 siRNA were transfected into LSCC cell lines Hep-2 and TU-177 to observe malignant behavior. miR-204-5p mimics were injected into Hep-2 or TU-177 xenograft tumors in nude mice to examine tumor growth.Results: The miR-204-5p mRNA level was lower in all 43 LSCC samples than in the ANM samples, but the FOXC1 level was higher in the LSCC samples than in the ANM samples. The miR-204-5p level was lower for stage III and IV cancer and lymph node N+ status samples than for stage I and II cancer and N0 status samples. FOXC1 mRNA and protein levels were higher for N+ than for N0 LSCC. The miR-204-5p mRNA levels were lower in Hep-2 and TU-177 cells than in ANM tissues, but FOXC1 mRNA levels were higher in Hep-2 and TU-177 cells than in ANM tissues. Dual-luciferase reporter assays demonstrated the targeted regulatory effects of miR-204-5p on the FOXC1 3' UTR. Cell proliferation and colony formation was facilitated with miR-204-5p mimics and FOXC1 siRNA, with weaker cell migration and invasion than the controls. Moreover, miR-204-5p overexpression or FOXC1 knockdown inhibited the EMT process in LSCC cells. In vivo experiments demonstrated that injection of miR-204-5p into Hep-2 and TU-177 xenograft tumors in nude mice significantly inhibited tumor growth. Conclusions: miR-204-5p is involved in the invasion and metastasis of LSCC. It has a targeted regulatory effect on FOXC1 expression; malignant LSCC behaviors, including cell proliferation, invasion, and metastasis, are suppressed, and tumor growth in vivo is inhibited. This suggests that miR-204-5p may be a target for molecular therapy of LSCC in the future.

Dataset Information

Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.

Publications

Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets