Prognostic Impact of Vitamin B6 Metabolism in Lung Cancer

• DOI: 10.1016/j.celrep.2012.06.017
• Publication Date: 2012-07-26T15:26:23Z
• Authors: Lorenzo Galluzzi; Ilio Vitale; Laura Senovilla; Ken André Olaussen; Guillaume Pinna; Tobias Eisenberg; Aïcha Goubar; Isabelle Martins; Judith Michels; Gueorgui Kratassiouk; Didac Carmona-Gut...; Marie Scoazec; Erika Vacchelli; Frederic Schlemmer; Oliver Kepp; Shensi Shen; Maximilien Tailler; Mireia Niso-Santano; Eugenia Morselli; Alfredo Criollo; Sandy Adjemian; Mohamed Jemaà; Kariman Chaba; Claire Pailleret; Mickaël Michaud; Federico Pietrocola; Nicolas Tajeddine; Thibault de La Mo...; Natalia Araujo; Nadya Morozova; Thomas Robert; Hugues Ripoche; Frederic Commo; Benjamin Besse; Pierre Validire; Pierre Fouret; Angélique Robin; Nicolas Dorvault; Philippe Girard; Sébastien Gouy; Patricia Pautier; Nora Jägemann; Ann-Christin Nickel; Sabrina Marsili; Caroline Paccard; Nicolas Servant; Philippe Hupé; Carmen Behrens; Parviz Behnam-Mot...; Kimitoshi Kohno; Isabelle Cremer; Diane Damotte; Marco Alifano; Øivind Midttun; Per Magne Ueland; Vladimir Lazar; Philippe Dessen; Hans Zischka; Etienne Chatelut; Maria Castedo; Frank Madeo; Emmanuel Barillot; Juergen Thomale; Ignacio Ivan Wistuba; Catherine Sautès-...; Laurence Zitvogel; Jean-Charles Soria; Annick Harel-Bellan; Guido Kroemer
• Keywords: Adult; Male; Lung Neoplasms; QH301-705.5; Medizin; 610; Antineoplastic Agents; Apoptosis; Disease-Free Survival; Gene Expression Regulation, Enzymologic; Cohort Studies; Mice; 03 medical and health sciences; Carcinoma, Non-Small-Cell Lung; Animals; Humans; Biology (General); Pyridoxal Kinase; Aged; Aged, 80 and over; 0303 health sciences; Middle Aged; Vitamin B 6; Neoplasm Proteins; 3. Good health; Survival Rate; Gene Expression Regulation, Neoplastic; Female; Cisplatin; Genome-Wide Association Study

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.