SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt Goutam Kumar Tanti *, 1 , Shweta Pandey, Shyamal K. Goswami * School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India article info Article history: Received 29 April 2015 Accepted 18 May 2015 Available online xxx Keywords: Striatin SG2NA Auto-antigen Akt DJ-1 Cancer abstract SG2NA in association with striatin and zinedin forms a striatin family of WD-40 repeat proteins. This family of proteins functions as scaffold in different signal transduction pathways. They also act as a regulatory subunit of protein phosphatase 2A. We have shown that SG2NA which evolved first in the metazoan evolution among the striatin family members expresses different isoforms generated out of alternative splicing. We have also shown that SG2NA protects cells from oxidative stress by recruiting DJ- 1 and Akt to mitochondria and membrane in the post-mitotic neuronal cells. DJ-1 is both cancer and Parkinson's disease related protein. In the present study we have shown that SG2NA protects DJ-1 from proteasomal degradation in cancer cells. Hence, downregulation of SG2NA reduces DJ-1/Akt colocali- zation in cancer cells resulting in the reduction of anchorage dependent and independent growth. Thus SG2NA enhances cancer cell survival. Reactive oxygen species enhances SG2NA, DJ-1 and Akt trimeri- zation. Removal of the reactive oxygen species by N-acetyl-cysteine thus reduces cancer cell growth. © 2015 Elsevier Inc. All rights reserved. 1. Introduction SG2NA was initially characterized as a nuclear localized tumor antigen whose expression is augmented during S to G2 phases of cell cycle [1,2]. Together with striatin and zinedin it forms striatin sub-family of WD-40 repeat superfamily [3]. Among these three members, SG2NA was the earliest to evolve [4]. Striatin family members act as the B 000 subunit of the heterotrimeric protein phosphatase 2A complex [5,6]. We have reported earlier that SG2NA has several isoforms generated out of alternative splicing [7]. Expression profile of SG2NAs in tissues changes with stages of embryonic development and post-natal aging [7,8,9]. Expression of SG2NA is epigenetically regulated by Brg-1 [10]. Recently, we found that SG2NA recruits DJ-1 and Akt to plasma membrane and mitochondria to protect cells from oxidative stress [11]. Like SG2NA, DJ-1 was also discovered as an oncogene that in cooperation with ras transforms NIH3T3 cells [12]. Its expression is augmented in prostate, lung, breast, renal, hepatocellular, ovarian, acute leukemia, cervical, papillary, thyroid cancer and squamous cell carcinomas [13,14]. It transforms NIH3T3 cells by directly interacting with the SV-40 large T antigen [15]. DJ-1 acti- vates Akt signaling by direct interaction and inhibition of PTEN [16,17]. It also can sense increased generation of reactive oxygen species (ROS); thus it acts as redox-sensitive chaperone and scavenge excess ROS, enhancing resistance against oxidative stress [18]. Akt is activated by several extra cellular signals including growth factors and by oncogenic mutations [19]. Activated Akt plays crucial physiological functions in cell proliferation, meta- bolism and stress responses. Its activity is tightly regulated by different combinations of kinases and phosphatases [19]. It remains in an inactive state due to an intramolecular interaction between the PH and the kinase domain. Various growth signals activate Phosphatidylinositol-3-kinases (PI3Ks) that in turn phosphorylate phosphatidylinositol-4, 5-bisphosphate (PIP2) to phosphatidylinositol-3, 4, 5-bisphosphate (PIP3) [20]. Akt simultaneously interacts with PIP3 and PDK-1, changing its conformation. PDK-1 then phsophorylates Akt at T308, inducing its activity [20]. However, for complete activation, it also needs to be phosphorylated at S473 though the mechanisms are not fully understood yet. A number of recent studies have shown * Corresponding authors. E-mail address: goutamjnu@hotmail.com (G.K. Tanti). 1 Present address: Neuro-Kopf-Zentrum, Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Muenchen, Germany. Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc http://dx.doi.org/10.1016/j.bbrc.2015.05.069 0006-291X/© 2015 Elsevier Inc. All rights reserved. Biochemical and Biophysical Research Communications xxx (2015) 1e8 Please cite this article in press as: G.K. Tanti, et al., SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt, Biochemical and Biophysical Research Communications (2015), http://dx.doi.org/10.1016/j.bbrc.2015.05.069