Aasia O Rehman1, Cun-yu Wang. 1. Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, CA 90095-1668, USA.
Abstract
AIM: To determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion. METHODOLOGY: A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA). RESULTS: We show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC. CONCLUSION: The CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.
AIM: To determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion. METHODOLOGY: A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA). RESULTS: We show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC. CONCLUSION: The CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.
Authors: Audrey N Jajosky; James E Coad; Jeffrey A Vos; Karen H Martin; Jamie R Senft; Sharon L Wenger; Laura F Gibson Journal: Stem Cells Transl Med Date: 2014-05-22 Impact factor: 6.940
Authors: Phillip C Delekta; Ingrid J Apel; Shufang Gu; Katy Siu; Yoshiyuki Hattori; Linda M McAllister-Lucas; Peter C Lucas Journal: J Biol Chem Date: 2010-11-01 Impact factor: 5.157
Authors: Peter C Lucas; Linda M McAllister-Lucas; J Randall McAuley; Kelly M Bailey; Prasanna Ekambaram; Linda R Klei; Heejae Kang; Dong Hu; Tanner J Freeman; Vincent J Concel; Nathaniel E Hubel; Jia-Ying Lloyd Lee; Hanna B Klei; Jing Cheng; Preethiya Sekar; Rachel E Bridwell; Lidija Covic Journal: Oncogene Date: 2019-08-16 Impact factor: 9.867