Hypoxic Adaptation and Arsenic Trioxide Treatment in Small Cell Lung Carcinoma
Author
Summary, in English
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.
Department/s
- Department of Translational Medicine
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:99
Full text
Document type
Dissertation
Publisher
Molecular Medicine
Topic
- Cancer and Oncology
Keywords
- small cell lung carcinoma
- arsenic trioxide
- hypoxia
- hypoxia-inducible factors
- survival
- proliferation
- glycolysis
- glutamine metabolism
- MYC
Status
Published
Supervisor
- Sven Påhlman
- Helen Pettersson
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87449-71-0
Defence date
27 September 2013
Defence time
09:15
Defence place
Forum conference room, Ideon Agora, Scheelevägen 15, Lund
Opponent
- Ola Nilsson (M.D., Ph.D.)