Proapoptotic Action of p53-Tom5 in p53-Resistant A549 Human Non-small Cell Lung Cancer Cells through Direct Mitochondrial Dysfunction

• Published in: Biological & pharmaceutical bulletin Vol. 34; no. 4; pp. 551 - 554
• Main Authors: Umemoto, Takuya, Asai, Tomohiro, Hirashima, Koji, Shimizu, Kosuke, Mihara, Motohiro, Yamamoto, Koji, Kubota, Koji, Miyagawa, Shin-ichi, Oku, Naoto
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2011; Japan Science and Technology Agency
• Subjects: alternative reading frame; Apoptosis; Biological Transport; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Carrier Proteins - therapeutic use; Cell Proliferation; Cytochromes c - metabolism; DNA; Drug Resistance, Neoplasm; gene delivery system; gene therapy; Gene Transfer Techniques; Genetic Therapy; Humans; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Membrane Transport Proteins - metabolism; Membrane Transport Proteins - therapeutic use; mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - metabolism; Mitochondrial Proteins - therapeutic use; p53-Tom5; Plasmids; Reading Frames; Transfection; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - therapeutic use
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.34.551

Transcription-dependent apoptosis triggered by p53 hardly occurs in alternative reading frame (ARF)-null cancer cells. Loss of ARF leads to hyperactivation of murine double minute 2 (MDM2), resulting in the degradation of p53. In the present study, A549 (ARF-null) human non-small lung cancer cells were transfected with a plasmid DNA encoding human wild-type p53 and the mitochondrial transmembrane domain of Tom5 (p53-Tom5) for delivering p53 to mitochondria. As a result, p53-Tom5 exclusively localized at mitochondria in A549 cells and suppressed the proliferation of them, whereas wild-type p53 did not. In addition, mitochondrial dysfunction and release of cytochrome c were induced by p53-Tom5 in A549 cells. These data suggest that p53-Tom5 suppressed the proliferation of A549 cells through direct mitochondrial dysfunction.