Original Paper

Apoptosis

, Volume 13, Issue 12, pp 1439-1449

Regulation of IGFBP6 gene and protein is mediated by the inverse expression and function of c-jun N-terminal kinase (JNK) and NFκB in a model of oral tumor cells

  • Nicholas A. CacalanoAffiliated withDepartment of Radiation Oncology, UCLA School of Dentistry and Medicine
  • , David LeAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine
  • , Avina ParanjpeAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine
  • , Mei-ying WangAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine
  • , Augustine FernandezAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine
  • , Tandik EvazyanAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine
  • , No-Hee ParkAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine
  • , Anahid JewettAffiliated withThe Jane and Jerry Weintraub Center for Reconstructive Biotechnology, The Jonsson Comprehensive Cancer Center (JCCC), Dental Research Institute, Division of Oral Biology and Medicine, UCLA School of Dentistry and Medicine Email author 

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Abstract

The aim of this study is to identify potential gene and protein targets when nuclear factor kappa B (NFκB) and c-jun N-terminal kinase (JNK) were inversely expressed in oral tumors. To determine which genes were regulated synergistically by the inverse expression of NFκB and JNK, a pathway specific microarray analysis was performed. While either inhibition of NFκB or activation of JNK alone was unable to affect the IGFBP6 gene expression in microarray analysis, concomitant increase in JNK activation in the presence of NFκB inhibition increased the expression of this gene significantly. Synergistic increase in IGFBP6 gene expression was also confirmed by RT-PCR and Northern blot analysis of transfected cells. Accordingly, the levels of IGFBP6 protein secretion rose synergistically when JNK was over-expressed in NFκB knock down cells. In addition, increased expression of JNK in the absence of NFκB resulted in a significant induction of cell death in oral tumors when either left untreated or treated with TNF-α and TPA. Moreover, when JNK was inhibited by dominant negative JNK (APF), a significant decrease in cell death could be observed in TNF-α and TPA treated NFκB knock down oral tumors. Therefore, increased induction of IGFBP6 gene or protein expression in oral tumors could be regarded as a potential predictive marker of tumor sensitivity and could be used for prognostic purposes, since a significant correlation could be observed between increased induction of apoptotic cell death and elevated levels of IGFBP6 in these tumors.

Keywords

Apoptosis NFκB IκB TNF-α JNK