Role of A-Kinase anchor protein (AKAP4) in growth and survival of ovarian cancer cells

  • Kumar V
  • Jagadish N
  • Suri A
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Abstract

// Vikash Kumar 1 , Nirmala Jagadish 1 and Anil Suri 1 1 Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, 110067, New Delhi, India Correspondence to: Anil Suri, email: anil@nii.res.in Keywords: AKAP4, PKA, reactive oxygen species, s-phase arrest, apoptosis Received: December 29, 2016      Accepted: May 10, 2017      Published: May 24, 2017 ABSTRACT Ovarian cancer represents one of the most common malignancies among women with very high mortality rate worldwide. A-kinase anchor protein 4 (AKAP4), a unique cancer testis (CT) antigen has been shown to be associated with various malignant properties of cancer cells. However, its involvement in various molecular pathways in ovarian cancer remains unknown. In present investigation, employing gene silencing approach, we examined the role of AKAP4 in cell cycle, apoptosis and epithelial-mesenchymal transition (EMT). Further, we also investigated the effect of ablation of AKAP4 on tumor growth in SCID mice ovarian cancer xenograft mouse model. Our results showed that ablation of AKAP4 resulted in increased reactive oxygen species (ROS) generation, DNA damage, cell cycle arrest and apoptosis in ovarian cancer cells. AKAP4 knockdown lead to degradation of protien kinase A (PKA) which was rescued by proteosome inhibitor MG-132. ROS quencher N-acetyl cysteine (NAC) treatment rescued cell cycle arrest and resumed cell division. Subsequently, increased expression of pro-apoptotic molecules and decreased expression of pro-survival/anti-apoptotic factors was observed. As a result of AKAP4 depletion, DNA damage response proteins p-γH2AX, p-ATM and p21 were upregulated. Also, knockdown of CREB resulted in similar findings. Further, PKA inhibitor (H89) and oxidative stress resulted in similar phenotype of ovarian cancer cells as observed in AKAP4 ablated cells. Collectively, for the first time our data showed the involvement of AKAP4 in PKA degradation and perturbed signaling through PKA-CREB axis in AKAP4 ablated ovarian cancer cells.

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Kumar, V., Jagadish, N., & Suri, A. (2017). Role of A-Kinase anchor protein (AKAP4) in growth and survival of ovarian cancer cells. Oncotarget, 8(32). https://doi.org/10.18632/oncotarget.18163

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