Targeting Glioma Stem Cells by Functional Inhibition of Dynamin 2: A Novel Treatment Strategy for Glioblastoma

Luwor, Rodney B.; Morokoff, Andrew; Amiridis, Stephanie; D'Abaco, Giovanna M.; Paradiso, Lucy; Stylli, Stanley S.; Nguyen, Huy; Tarleton, Mark; Young, Kelly A.; O’Brien, Terence J.; Robinson, Phillip J.; Chircop, Megan; McCluskey, Adam; Jones, Nigel C.

doi:10.1080/07357907.2019.1582060

Cited by 19 publications

(13 citation statements)

References 45 publications

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“…Importantly, the efficacy of Dynole 34-2 irrespective of activating mutations of growth factor-induced signalling could be explained by the importance of Dynamin for the CXCR4/CXCL12-mediated response to the microenvironment, which promotes survival of LSCs through the activation of the MAPK and AKT signalling pathways in acute leukemia 15,19,70 . Our data support previous reports confirming the efficacy of Dynole 34-2 to inhibit internalization of signalling receptors and downstream signal transduction in different malignancies 35,71 . However, further genetic molecular assays with cytokine-dependent cells lacking Dynamin or expressing specific mutants of Dynamin will be required to characterize the specificity of Dynole 34-2 for targeting Dynamin in the biological context of leukemia.…”

Section: Discussionsupporting

confidence: 93%

Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

et al. 2020

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Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.

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Section: Discussionsupporting

confidence: 93%

Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

et al. 2020

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“…Indeed, a clinical trial is underway utilizing a small molecule HIF-2α inhibitor to teat glioblastoma [7] . Furthermore, as our results indicate a modest additive effect with temozolomide in cell killing and complementary influences on CSC differentiation status, combination therapies that combine chemotherapeutics with HIF-2α silencing or inhibition are an attractive avenue in the pursuit of a therapy that can eradicate the CSCs that drive recurrence of malignant cancers such as glioblastoma [33,34] .…”

Section: Discussionmentioning

confidence: 79%

Gene silencing of HIF-2α disrupts glioblastoma stem cell phenotype

Nusblat¹,

Tanna²,

Roth³

2020

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Aim: Improved treatment strategies are desperately needed for eradicating cancer stem cells (CSCs), which drive malignancy and recurrence in glioblastoma multiforme. Hypoxic regions within the tumor microenvironment help maintain and promote the proliferation of CSCs. Here, we explored the effects of silencing hypoxia inducible factor-2α (HIF-2α) because of its specificity for CSCs within the hypoxic environment. Methods: Cancer stem cell neurospheres were formed by enriching from both the glioblastoma cell line U87 and from brain tumor stem cells isolated directly from human brain tumors. Silencing of human HIF-2α was performed using both commercial and in-house transfection of a validated short interfering RNA, with all results compared to an established non-silencing control short interfering RNA. Silencing of HIF-2α was established by Western blotting, and phenotypic effects were assayed by cell migration assays, cell viability measurements, and immunofluorescence staining of differentiation markers. Results: Transfection with either our previously reported pH-sensitive, cationic amphiphilic macromolecule-based delivery system or Lipofectamine was similarly effective in silencing HIF-2α. The chemotherapeutic resistance and neurosphere formation were reduced when HIF-2α was silenced. Migratory capacities in the presence of macrophage conditioned media were modulated. HIF-2α silencing was complementary to temozolomide treatment in producing phenotypic rather than cytotoxic effects. Conclusion: HIF-2α silencing under hypoxia inhibited CSC phenotypes while promoting differentiated cell phenotypes and is complementary to existing DNA alkylating treatments in inhibiting glioma CSC activity.

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“…For instance, dynamin‐2 is a GTPase responsible for endocytosis in the eukaryotic cell. It has been documented that inhibition of dynamin‐2 suppressed glioblastoma cell line proliferation and prevented glioma stem cells from neurosphere formation and migration [33]. However, whether these proteins involve in the HCC tumor growth mediated by HSPA12A should be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Heat‐Shock protein A12A is a novel PCNA‐binding protein and promotes hepatocellular carcinoma growth

et al. 2020

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Proliferating cell nuclear antigen (PCNA) plays a pivotal role in cancer development and progression. However, the long-term dismal prognosis of HCC mandates more investigation to identify novel regulators in HCC pathogenesis. Heat-shock protein A12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that HCC cells showed increased HSPA12A expression, and overexpression of HSPA12A promoted HCC growth and angiogenesis in mice. Gain-and loss-of-functional studies demonstrated that the proliferation of HCC HepG2 cells, as well as b-catenin expression and nuclear translocation, was promoted by HSPA12A overexpression, but in turn suppressed by HSPA12A knockdown. HSPA12A did not impact PCNA expression; however, mass spectrometry and co-immunoprecipitation immunoblotting analysis revealed that HSPA12A directly binds to PCNA and promotes its trimerization, which is an essential functional conformation of PCNA for carcinogenesis. Importantly, PCNA inhibition by PCNA-I1 reversed the HSPA12A-mediated HepG2 cell differentiation. These findings indicate that HSPA12A is a novel regulator of HCC cell proliferation and tumor growth through binding to PCNA for its trimerization. HSPA12A inhibition might represent a viable strategy for the management of HCC in humans.

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Targeting Glioma Stem Cells by Functional Inhibition of Dynamin 2: A Novel Treatment Strategy for Glioblastoma

Cited by 19 publications

References 45 publications

Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Gene silencing of HIF-2α disrupts glioblastoma stem cell phenotype

Heat‐Shock protein A12A is a novel PCNA‐binding protein and promotes hepatocellular carcinoma growth

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