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

// Matilda Munksgaard Thoren 1 , Marica Vaapil 1, 5 , Johan Staaf 2 , Maria Planck 2, 3 , Martin E. Johansson 4 , Sofie Mohlin 1 and Sven Pahlman 1 1 Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, Lund, Sweden 2 Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE Lund, Sweden 3 Department of Oncology, Skane University Hospital, SE Lund, Sweden 4 Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skane University Hospital, Malmo, Sweden 5 Current address: Biosciences Area, Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA Correspondence to: Sven Pahlman, email: Sven.pahlman@med.lu.se Keywords: small cell lung carcinoma (SCLC), hypoxia, hypoxia-inducible factor, MYC, glutamine Received: November 23, 2016      Accepted: March 29, 2017      Published: April 06, 2017 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 .