| 1. |
- Hamidian, Arash, et al.
(författare)
-
Differential regulation of HIF-1α and HIF-2α in neuroblastoma: Estrogen-related receptor alpha (ERRα) regulates HIF2A transcription and correlates to poor outcome.
- 2015
-
Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 461:3, s. 560-567
-
Tidskriftsartikel (refereegranskat)abstract
- Hypoxia-inducible factors (HIFs) are differentially regulated in tumor cells. While the current paradigm supports post-translational regulation of the HIF-α subunits, we recently showed that hypoxic HIF-2α is also transcriptionally regulated via insulin-like growth factor (IGF)-II in the childhood tumor neuroblastoma. Here, we demonstrate that transcriptional regulation of HIF-2α seems to be restricted to neural cell-derived tumors, while HIF-1α is canonically regulated at the post-translational level uniformly across different tumor forms. Enhanced expression of HIF2A mRNA at hypoxia is due to de novo transcription rather than increased mRNA stability, and chemical stabilization of the HIF-α proteins at oxygen-rich conditions unexpectedly leads to increased HIF2A transcription. The enhanced HIF2A levels do not seem to be dependent on active HIF-1. Using a transcriptome array approach, we identified members of the Peroxisome proliferator-activated receptor gamma coactivator (PGC)/Estrogen-related receptor (ERR) complex families as potential regulators of HIF2A. Knockdown or inhibition of one of the members, ERRα, leads to decreased expression of HIF2A, and high expression of the ERRα gene ESRRA correlates with poor overall and progression-free survival in a clinical neuroblastoma material consisting of 88 tumors. Thus, targeting of ERRα and pathways regulating transcriptional HIF-2α are promising therapeutic avenues in neuroblastoma.
|
|
| 2. |
- Knudsen, Kasper Jermiin, et al.
(författare)
-
ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.
- 2015
-
Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 29:18, s. 1915-1929
-
Tidskriftsartikel (refereegranskat)abstract
- The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.
|
|
| 3. |
- Pettersson, Helen, et al.
(författare)
-
Arsenic trioxide is highly cytotoxic to small cell lung carcinoma cells.
- 2009
-
Ingår i: Molecular Cancer Therapeutics. - 1538-8514 .- 1535-7163. ; 8:1, s. 160-170
-
Tidskriftsartikel (refereegranskat)abstract
- Small cell lung carcinoma (SCLC) is an extremely aggressive form of cancer and current treatment protocols are insufficient. SCLC have neuroendocrine characteristics and show phenotypical similarities to the childhood tumor neuroblastoma. As multidrug-resistant neuroblastoma cells are highly sensitive to arsenic trioxide (As2O3) in vitro and in vivo, we here studied the cytotoxic effects of As2O3 on SCLC cells. As2O3 induced pronounced cell death in SCLC cells at clinically relevant concentrations, and also at hypoxia. SCLC cells were more sensitive than non-SCLC cells to As2O3. Cell death was mainly due to necrosis, although apoptotic responses were also seen. A significant in vivo effect of As2O3 on SCLC growth was shown in a nude mice-xenograft model, although a fraction of the treated tumor-bearing animals did not respond. The nonresponding SCLC tumors differed in morphology and cell organization compared with treatment-responsive tumors, which in turn, showed decreased vascularization and higher expression of neuroendocrine markers compared with control tumors. Our results suggest a potential clinical application of As2O3 in SCLC therapy. In addition to cell death induction, antiangiogenic induction of differentiation may also be part of the in vivo effect of As2O3 on SCLC growth, as suggested by an increase in neuroendocrine markers in cultured cells.
|
|
| 4. |
|
|
| 5. |
- Thorén, Matilda
(författare)
-
Hypoxic Adaptation and Arsenic Trioxide Treatment in Small Cell Lung Carcinoma
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Small cell lung carcinoma (SCLC) is a very aggressive solid tumor and is often widely metastasized by the time of diagnosis. Despite good response to the initial chemotherapy, SCLC cells often develop multidrug resistance to conventionally used chemotherapeutic drugs, which cause almost all SCLC tumors to relapse. The 5-year survival rate for patients with limited disease is around 20% while it is only a few percent for patients with a disseminating disease. Arsenic trioxide (As2O3) is one of the oldest medicines used for treatment of different diseases and it is today used as first-line treatment for patients with relapsed or refractory acute promyelocytic leukemia. Here, we demonstrate that As2O3 is cytotoxic to SCLC cells and xenotransplanted SCLC tumors at clinically relevant concentrations and the effect is also sustained at hypoxic conditions. Areas of low oxygen tensions, hypoxia, are a common characteristic in solid tumors and are associated with aggressive tumor behavior, treatment resistance and poor outcome in several tumor forms. In response to hypoxia, tumor cells induce a transcriptional shift which is mainly regulated by the transcription factors hypoxia-inducible factor (HIF)-1 and HIF-2. HIF proteins consist of two subunits, an oxygen-regulated α-subunit and a constitutively expressed β-subunit. Previous reports have shown that the transcription factors are differentially regulated over time; HIF-1 primarily mediates the acute hypoxic response, whereas HIF-2 dominates during more chronic phases of hypoxia. We found that SCLC tumor specimens and cells lack expression of HIF-2α protein while HIF-1α is expressed at both acute and prolonged hypoxia. In addition, SCLC cells have a high adaptive capacity to hypoxia including a high proliferation rate and low cell death, even though we demonstrated a modest induction of well-known hypoxia-driven genes. We further show that knockdown of HIF1A using siRNA or shRNA, is not significantly affecting the cell viability of cultured SCLC cells at moderate and severe hypoxia or tumor take and tumor growth in SCLC xenografts. We found that SCLC cells are dependent on glutamine metabolism for cell viability and proliferation, in a HIF-independent fashion. The SCLC cells used here are MYC and MYCL amplified and MYC overexpression is known to stimulate glutaminolysis and lipogenesis. In HIF1A repressed cells that overexpress MYC, genes involved in these pathways are further up-regulated at hypoxic conditions. Taken together, our data indicate that the adaptive capacity to hypoxia is partially HIF-independent in MYC amplified SCLC cells.
|
|
| 6. |
- Thorén, Matilda Munksgaard, et al.
(författare)
-
Integrin α10, a novel therapeutic target in glioblastoma, regulates cell migration, proliferation, and survival
- 2019
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 11:4
-
Tidskriftsartikel (refereegranskat)abstract
- New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10Β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10Β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin a10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10Β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10Β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
|
|
| 7. |
- Thorén, Matilda Munksgaard, et al.
(författare)
-
Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells
- 2017
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:30, s. 48983-48995
-
Tidskriftsartikel (refereegranskat)abstract
- We previously demonstrated that small cell lung carcinoma (SCLC) cells lack HIF-2α protein expression, whereas HIF-1α in these cells is expressed at both acute and prolonged hypoxia. Here we show that low HIF2A expression correlates with high expression of MYC genes. Knockdown of HIF1A expression had no or limited effect on cell survival and growth in vitro. Unexpectedly, hypoxic ATP levels were not affected by HIF-1α knockdown and SCLC cell viability did not decrease upon glucose deprivation. In line with these in vitro data, xenograft tumor-take and growth were not significantly affected by repressed HIF1A expression. Glutamine withdrawal drastically decreased SCLC cell proliferation and increased cell death at normoxia and hypoxia in a HIF-independent fashion and the dependence on glutaminolysis was linked to amplification of either MYC or MYCL. Downregulation of GLS expression, regulating the first step of the glutaminolysis pathway, in MYC/MYCL overexpressing SCLC cells resulted in both impaired growth and increased cell death. Our results suggest that MYC/MYCL overexpression in SCLC cells overrides the need of HIF-1 activity in response to hypoxia by inducing glutaminolysis and lipogenesis. Targeting the glutaminolysis pathway might hence be a novel approach to selectively kill MYC amplified SCLC cells in vivo.
|
|
| 8. |
- Zirath, Hanna, et al.
(författare)
-
MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:25, s. 10258-10263
-
Tidskriftsartikel (refereegranskat)abstract
- The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.
|
|
