Effective enrichment of prostate cancer stem cells from spheres in a suspension culture system

Fan, Xiaolong; Liu, Shanying; Su, Fang; Pan, Qiuhui; Lin, Tianxin

doi:10.1016/j.urolonc.2010.03.019

Cited by 53 publications

(46 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, maximal secondary and tertiary SSSs in 0.1 μM MLN4924 culture were significantly larger than that of primary SSSs (Fig. S1G, red), suggesting a higher percentage of CSCs in TSs than in monolayer culture, which is consistent with a previous report (19).…”

Section: Mln4924 Stimulates Self-renewal and Increases The Level Of Stemsupporting

confidence: 92%

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Zhou

Tan

Nyati

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells. These stimulatory effects are attributable to (i) c-MYC accumulation via blocking its degradation and (ii) continued activation of EGFR (epidermal growth factor receptor) and its downstream pathways, including PI3K/AKT/mammalian target of rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. Finally, MLN4924 accelerates EGF-mediated skin wound healing in mouse and stimulates cell migration in an in vitro culture setting. Taking these data together, our study reveals that neddylation modification could regulate stem cell proliferation and differentiation and that a low dose of MLN4924 might have a therapeutic value for stem cell therapy and tissue regeneration.MLN4924 | neddylation | EGFR | stem cell | wound healing I n cells, homeostasis is reached by a fine balance between the rates of protein synthesis and degradation. The process of protein degradation by the ubiquitin-proteasome system (UPS) involves two sequential steps: (i) ubiquitylation catalyzed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) and (ii) degradation catalyzed by 26S proteasome (1). Abnormal UPS activity abrogates the homeostasis and is associated with many human diseases, including cancer (2, 3). Bortezomib, the first Food and Drug Administration-approved proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma (4), possesses significant cytotoxicity against normal cells due to its universal inhibition of the UPS (5). This stimulated an intensive search for inhibitors targeting the enzymes upstream of the proteasome for improved specificity.Cullin-RING ligases (CRLs), consisting of scaffold cullins, adaptor proteins, substrate-recognizing receptors, and RING finger proteins, are the largest family of E3 ubiquitin ligases and are responsible for the ubiquitylation of about 20% of all cellular proteins (6, 7). The activity of CRLs requires neddylation of the cullin proteins (8, 9), a ubiquitylation-like process, which is sequentially catalyzed by three enzymes: a NEDD8-activating enzyme (NAE or E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligase (E3). Abnormal elevation of CRL activity has been found in multiple human cancers, which makes them favorable targets for cancer treatment (10, 11).MLN4924 was descried in 2009 as the first-in-class NAE inhibitor exclusively in the application for cancer treatment by inactivation of CRLs via blockage of cullin neddylation (7). Since the initial report, more than 150 p...

show abstract

Section: Mln4924 Stimulates Self-renewal and Increases The Level Of Stemsupporting

confidence: 92%

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Zhou

Tan

Nyati

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Similarly, the CD133 ϩ / CD117 high /ABCG2 high /nestin ϩ PCa cell subpopulation, isolated from the CWR22RV1 PCa cell line, was more resistant to the commonly used chemotherapeutic drugs, such as cisplatin, paclitaxel, and methotrexate, than the CD133 Ϫ /ABCG2 low cells (46). Early reports showed that the CD133 ϩ /CD44 ϩ PCa cells isolated from a non-adherent suspension of PC-3 cells are more resistant to cisplatin (47,48). Recently, Zhang et al (47) suggested that tumor sphere-forming PCa cells, which are characteristic of stem/progenitor cells, displayed higher chemoresistance when compared with adherent cells.…”

Section: Cd133mentioning

confidence: 99%

Increased Chemosensitivity via Targeting Testicular Nuclear Receptor 4 (TR4)-Oct4-Interleukin 1 Receptor Antagonist (IL1Ra) Axis in Prostate Cancer CD133+ Stem/Progenitor Cells to Battle Prostate Cancer

Yang

Ding

Luo

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: PCa stem/progenitor cells develop higher chemoresistance. Results: High TR4 levels in PCa stem/progenitor cells were shown to be critical in conferring chemoresistance to these cells. Conclusion: TR4-Oct4-IL1Ra signaling is important in conferring chemoresistance to PCa stem/progenitor cells. Significance: This finding suggests that targeting TR4 and its downstream molecules may be a better therapeutic approach to battle PCa stem/progenitor cell-originated chemoresistance.

show abstract

“…Recent lines of experimental evidence have revealed that the PC stem/progenitor cells, including side population (SP) of PC cells isolated by using the Hoechst dye efflux technique, exhibiting an AI phenotype and expressing high levels of ATP-binding cassette (ABC) multidrug transporters such as ABCG2, may be more resistant than their differentiated progenies and non-SP cells to the antihormonal and chemotherapeutic treatments (67)(68)(69)180). For example, it was observed that the nonadherent suspension culture of metastatic and AI PC3 cells under the form of prostaspheres resulted in an enrichment of CD133 + / CD44 + PC cells that are more resistance to cisplatin than adherent cells (68).…”

Section: Critical Implication Of Pc-and Metastasis-initiating Cells Amentioning

confidence: 99%

“…For example, it was observed that the nonadherent suspension culture of metastatic and AI PC3 cells under the form of prostaspheres resulted in an enrichment of CD133 + / CD44 + PC cells that are more resistance to cisplatin than adherent cells (68). Similarly, the highly tumorigenic CD133 + / CD117 high / ABCG2 high /nestin + PC cell subpopulation coexpressing Oct3/4, Nanog and Sox2 from the PC cell line 22RV1 was also more resistant to treatment with a variety of chemotherapeutic drugs such as cisplatin, paclitaxel, adriamycin, and methotrexate than the CD133 -/ABCG2 low 22RV1 cell fraction (67).…”

Section: Critical Implication Of Pc-and Metastasis-initiating Cells Amentioning

confidence: 99%

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Mimeault

Batra

2011

Mol Med

View full text Add to dashboard Cite

Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

show abstract

Effective enrichment of prostate cancer stem cells from spheres in a suspension culture system

Cited by 53 publications

References 22 publications

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

Increased Chemosensitivity via Targeting Testicular Nuclear Receptor 4 (TR4)-Oct4-Interleukin 1 Receptor Antagonist (IL1Ra) Axis in Prostate Cancer CD133+ Stem/Progenitor Cells to Battle Prostate Cancer

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Contact Info

Product

Resources

About