Two major "hallmarks" of all cancer cells include dysregulated cell cycle and inhibited apoptosis, both of which are also involved in adenovirus (Ad) infection. These two processes are primarily conducted by viral oncoproteins E1A and E1B. Since the function of viral E1 protein is similar to that of cancer cellular factors that promote proliferation and inhibit apoptosis, viruses with mutations in oncoprotein E1A and E1B can selectively replicate in cancer cells. One such mutant with deletion of E1B55K, known as dl1520, has been used in clinical trials documenting oncolytic effects. However, the mechanism of viral oncolytic replication has not been well characterized, and the therapeutic efficacy needs improvement. It is generally believed that the major role of E1B55K is to bind to and inhibit p53 activation, but many studies have documented that E1B55K-mediated p53 inactivation is not required for virus replication. Our laboratory has shown: (1) that the limited spread of mutant viruses in large tumors is a key factor in decreased therapeutic efficacy;(2) increased Ad E1A expression enhances virus-oncolytic replication;and (3) apoptosis caused by E1B deletion can partially decrease virus replication but does not change the final outcome of virus-mediated cancer killing. Our recent studies have revealed that E1B55K has a novel function in the induction of cyclin E and other cell cycle-related genes. Most importantly, we also observed that increased cyclin E expression is correlated with virus replication efficiency. E1B55K-induced cyclin E expression is required for virus replication in normal cells, but is not necessary in cancer cells. We hypothesize that E1B55K may target cellular factor(s) to increase cyclin E expression, and this factor(s) may already be activated in cancer cells. Thus, cyclin E dysregulation in cancer cells may be the molecular basis for oncolytic replication of E1B55K-deleted viruses. Our research team will (1) identify cellular factors targeted by E1B55K for cyclin E induction, (2) define the mechanism by which E1B55K activates cyclin E expression, and (3) determine the relationship between cyclin E overexpression and oncolytic replication of E1B-deleted viriuses. If we confirm that oncolytic replication relies on cyclin E expression and cell proliferation, patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy.
Adenoviruses lacking an important regulative protein-E1B55K-still can amplify in some cancer cells. Therefore, the E1B55K mutant dl1520 has been used in clinical trials. It is important to understand the E1B55K function and the selective replication of E1B55K-deleted dl1520 in cancer cells. Our recently published studies have revealed that E1B55K has a novel function in the induction of cyclin E expression, which is crucial for DNA replication. Cancer cells generally express high levels of cyclin E or have a dysregulation of the gene. We reason that viral E1B55K may activate some cellular factors that increase cyclin E expression for viral DNA replication. Cancer cells may already have the factors activated;therefore cancer cells do not require the E1B55K function. The study of this possibility is very important. If we confirm that mutated virus replication relies on cyclin E expression, patients with aggressively growing tumors and dysregulated cyclin E should greatly benefit from this adenoviral therapy. The long-term goal of this work is to increase the efficacy of oncolytic cancer gene therapy.
|Cheng, Pei-Hsin; Rao, Xiao-Mei; Duan, Xiaoxian et al. (2015) Virotherapy targeting cyclin E overexpression in tumors with adenovirus-enhanced cancer-selective promoter. J Mol Med (Berl) 93:211-23|
|Chen, Lan; Cheng, Pei-Hsin; Rao, Xiao-Mei et al. (2014) Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis. Cancer Biol Ther 15:1256-67|
|Cheng, Pei-Hsin; Lian, Serena; Zhao, Robin et al. (2013) Combination of autophagy inducer rapamycin and oncolytic adenovirus improves antitumor effect in cancer cells. Virol J 10:293|
|Cheng, Pei-Hsin; Rao, Xiao-Mei; McMasters, Kelly M et al. (2013) Molecular basis for viral selective replication in cancer cells: activation of CDK2 by adenovirus-induced cyclin E. PLoS One 8:e57340|
|Rodriguez-Rocha, Humberto; Gomez-Gutierrez, Jorge G; Garcia-Garcia, Aracely et al. (2011) Adenoviruses induce autophagy to promote virus replication and oncolysis. Virology 416:9-15|
|Gomez-Gutierrez, Jorge G; Garcia-Garcia, Aracely; Hao, Hongying et al. (2010) Adenovirus-mediated expression of truncated E2F-1 suppresses tumor growth in vitro and in vivo. Cancer 116:4420-32|
|Gomez-Gutierrez, Jorge G; Rao, Xiao-Mei; Garcia-Garcia, Aracely et al. (2010) Developing adenoviral vectors encoding therapeutic genes toxic to host cells: comparing binary and single-inducible vectors expressing truncated E2F-1. Virology 397:337-45|