American Association for Cancer Research
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Supplementary Figure 1 from Expression of a Truncated Active Form of VDAC1 in Lung Cancer Associates with Hypoxic Cell Survival and Correlates with Progression to Chemotherapy Resistance

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posted on 2023-03-30, 21:27 authored by M. Christiane Brahimi-Horn, Danya Ben-Hail, Marius Ilie, Pierre Gounon, Matthieu Rouleau, Véronique Hofman, Jérôme Doyen, Bernard Mari, Varda Shoshan-Barmatz, Paul Hofman, Jacques Pouysségur, Nathalie M. Mazure

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ARTICLE ABSTRACT

Resistance to chemotherapy-induced apoptosis of tumor cells represents a major hurdle to efficient cancer therapy. Although resistance is a characteristic of tumor cells that evolve in a low oxygen environment (hypoxia), the mechanisms involved remain elusive. We observed that mitochondria of certain hypoxic cells take on an enlarged appearance with reorganized cristae. In these cells, we found that a major mitochondrial protein regulating metabolism and apoptosis, the voltage-dependent anion channel 1 (VDAC1), was linked to chemoresistance when in a truncated (VDAC1-ΔC) but active form. The formation of truncated VDAC1, which had a similar channel activity and voltage dependency as full-length, was hypoxia-inducible factor-1 (HIF-1)-dependent and could be inhibited in the presence of the tetracycline antibiotics doxycycline and minocycline, known inhibitors of metalloproteases. Its formation was also reversible upon cell reoxygenation and associated with cell survival through binding to the antiapoptotic protein hexokinase. Hypoxic cells containing VDAC1-ΔC were less sensitive to staurosporine- and etoposide-induced cell death, and silencing of VDAC1-ΔC or treatment with the tetracycline antibiotics restored sensitivity. Clinically, VDAC1-ΔC was detected in tumor tissues of patients with lung adenocarcinomas and was found more frequently in large and late-stage tumors. Together, our findings show that via induction of VDAC1-ΔC, HIF-1 confers selective protection from apoptosis that allows maintenance of ATP and cell survival in hypoxia. VDAC1-ΔC may also hold promise as a biomarker for tumor progression in chemotherapy-resistant patients. Cancer Res; 72(8); 2140–50. ©2012 AACR.