Downregulation of c-MYC Protein Levels Contributes to Cancer Cell Survival under Dual Deficiency of Oxygen and Glucose

Hiroaki Okuyama,Kikuya Kato,Masahiro Inoue,Tamaki Akashika,Hiroko Endo

doi:10.1158/0008-5472.can-10-2720

Hiroaki Okuyama, Kikuya Kato + Show 3 more

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https://doi.org/10.1158/0008-5472.can-10-2720

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Abstract

The c-MYC protein participates in energy-consuming processes such as proliferation and ribosome biosynthesis, and its expression is often dysregulated in human cancers. Cancer cells distant from blood vessels in solid tumors are in short supply of oxygen and nutrition yet can adapt to the microenvironment and survive under metabolic stress. The role and regulation of c-MYC protein in the tumor microenvironment of limited energy sources are poorly understood. Here, we show that c-MYC protein levels in cancer cells are strikingly reduced in the area distant from the blood vessels in vivo and also under oxygen- and glucose-deprived conditions in vitro. The rapid reduction of c-MYC protein levels requires low levels of both oxygen and glucose, and under these conditions, downregulation is mainly achieved by enhanced degradation. Suppression of c-MYC protein levels by small hairpin RNA decreases the necrotic cell death induced by oxygen and glucose deprivation. Thus, the environmental milieu regulates c-MYC protein levels, and downregulation of c-MYC might be a strategy for cancer cells to survive under conditions of limited energy sources.

Highlights

Most solid tumors contain substantially large hypoxic regions
We show that tumor cells in a region distant from blood vessels in vivo are metabolically inactive and that c-MYC protein levels are dramatically reduced in this area
Phosphorylated S6 (p-S6), downstream of mTOR and involved in ribosomal biogenesis, was detected only in the area proximal to the tumor vessels but not in the area distant from the tumor vessels (Fig. 1C). These results indicate that cancer cells proximal to the blood vessels are active in proliferation and metabolism, whereas cancer cells distant from the blood vessels are inactive

Summary

Introduction

Most solid tumors contain substantially large hypoxic regions. Hypoxic cancer cells are known to be resistant to chemotherapy and radiation, leading to a high risk of local recurrence and distant metastasis, which are associated with a poor clinical prognosis [1].Under hypoxic conditions, a transcription factor, hypoxia inducible factor-1a (HIF-1a), accumulates dramatically through inhibition of ubiquitination and proteasomal degradation [2]. Most solid tumors contain substantially large hypoxic regions. Hypoxic cancer cells are known to be resistant to chemotherapy and radiation, leading to a high risk of local recurrence and distant metastasis, which are associated with a poor clinical prognosis [1]. HIF-1 is a heterodimeric protein consisting of HIF-1a and HIF-1b subunits [3] and regulates the expression of hundreds of genes to promote angiogenesis, proliferation, and survival of hypoxic tumor cells [2]. Cancer cells show a high glycolytic rate even under aerobic conditions [4], and hypoxic cancer cells are challenged by a compound deficiency in energy substrates, including oxygen and glucose [2, 5].

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