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Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells

Thorén, Matilda Munksgaard LU ; Vaapil, Marica LU ; Staaf, Johan LU ; Planck, Maria LU ; Johansson, Martin E LU ; Mohlin, Sofie LU and Påhlman, Sven LU (2017) In Oncotarget 8(30). p.48983-48995
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
Oncotarget
volume
8
issue
30
pages
48983 - 48995
publisher
Impact Journals, LLC
external identifiers
  • wos:000406232400041
  • scopus:85025826530
ISSN
1949-2553
DOI
10.18632/oncotarget.16904
language
English
LU publication?
yes
id
7cc1b51e-d795-4b4c-9af4-a1424e559cc3
date added to LUP
2017-05-30 15:43:09
date last changed
2018-01-07 12:05:43
@article{7cc1b51e-d795-4b4c-9af4-a1424e559cc3,
  abstract     = {<p>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.</p>},
  author       = {Thorén, Matilda Munksgaard and Vaapil, Marica and Staaf, Johan and Planck, Maria and Johansson, Martin E and Mohlin, Sofie and Påhlman, Sven},
  issn         = {1949-2553},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {04},
  number       = {30},
  pages        = {48983--48995},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells},
  url          = {http://dx.doi.org/10.18632/oncotarget.16904},
  volume       = {8},
  year         = {2017},
}