Simultaneous inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNF alpha-mediated apoptosis

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Sanlioglu S., LULECI G., THOMAS K.

CANCER GENE THERAPY, cilt.8, sa.11, ss.897-905, 2001 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 8 Sayı: 11
  • Basım Tarihi: 2001
  • Doi Numarası: 10.1038/sj.cgt.7700394
  • Dergi Adı: CANCER GENE THERAPY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.897-905
  • Anahtar Kelimeler: TNF, NF kappa B, IKK, Rac1, cancer, gene therapy, NF-KAPPA-B, INEFFICIENT GENE-TRANSFER, GROWTH-FACTOR RECEPTOR, NECROSIS-FACTOR-ALPHA, CYSTIC-FIBROSIS, ADENOVIRUS VECTOR, AIRWAY EPITHELIA, SIGNALING COMPLEX, PROTEIN-KINASE, BETA SUBUNIT
  • Akdeniz Üniversitesi Adresli: Evet

Özet

Lung cancer is the most frequently occurring cancer in the world and causes more deaths in the United States than does colon, breast, and prostate cancer combined. Despite advances in treatment modalities including radiation, surgery, and chemotherapy, the overall survival in lung cancer remains low. The cytokine tumor necrosis factor alpha (TNF alpha) has been shown to regulate both apoptotic and antiapoptotic pathways. Activation of the transcription factor NF-kappaB appears to be the critical determinant of the antiapoptotic response to TNF alpha exposure in epithelial cells. A549 human lung carcinoma cells were infected with adenoviral constructs carrying dominant negative mutants of Rac1 and IKK or constitutively active mutant of Rac1, upstream effectors in TNF-mediated NF-kappaB activation. Cell death, apoptosis, and NF-kappaB activation were subsequently measured in response to TNF alpha exposure. Although TNF alpha alone had no cytotoxic effect, the expression of the dominant negative mutant of IKK beta (Ad.IKK beta KA) resulted in apoptotic cell death following TNFa exposure. Similarly, dominant negative mutant to Rac1 (Ad.N17Rac1) further sensitized A549 cells to IKK beta KA-mediated TNF alpha -induced cell death, Conversely, a dominant active form of Rac1 (Ad.V12Rac1) ameliorated the cell death response to concurrent IKK beta dominant negative mutant infection and TNF alpha exposure. These results suggest that concurrent inhibition of Rac1 and IKK pathways sensitizes lung cancer cells to TNF alpha -induced apoptosis.