Vitaly Polunovsky, PhD

Professor of Medicine
Contact Information

Cap-dependent translational control for cancer

Cancer cells differ from their normal counterparts in many ways. One important difference is tumor cells' requirement for increased synthesis of proteins  responsible for cellular growth and viability. In mammalian cells, most proteins are synthesized through a mechanism that requires a specific modification of genetic messengers (mRNAs) with a structure called a cap. Activity of the cap-dependent translation apparatus is commonly increased in many human tumors, including lung cancers.

In 1996, we discovered that enforced activation of cap-dependent translation rescues normal and cancer cells from programmed cell death. Later, we were able to demonstrate that targeted inhibition of cap-dependent protein synthesis decreases the viability of cancer cells and dramatically reduces their tumorigenicity. Our publication in Cancer Cell (Avdulov et al. 2004) established that aberrant activation of the translation initiation machinery is an essential step in the genesis and maintenance of the malignant phenotype in human breast cancer cells. We recently summarized the evidence that the cap-dependent translation initiation apparatus is a nodal point of convergence of oncogenic signals in human malignancy (Polunovsky and Bitterman, 2006).

In this publication, we expanded the existing paradigm of predominantly genomic, transcriptional and post-translational control of cancer gene expression by stressing the role of the translational step. However, how aberrant activation in the cap-dependent process could lead to a transformed phenotype remains unknown. Using the contemporary microarray methodology, we have recently discovered that pro-oncogenic activation of cap-dependent translation is associated with enhanced translational efficiency of genetic messenger encoding cell growth promoters, and decreased translation of growth inhibitors. Moreover, we found that many abnormally translated mRNAs contain specific regions that can be considered as candidate translational regulatory elements. Based on these findings, we hypothesized that many messenger molecules encoding potentially cancerous proteins harbor specific regulatory elements that interact with protein binding partners to enable coordinated alterations of their translational efficiency in response to activation of the translational apparatus by physiologically regulated or oncogenic cell growth signals. To test our hypothesis, we plan to apply microarray analysis to find messenger RNAs that are coordinately up-regulated or down-regulated in human breast cancer cells and identify the protein binding partners that enable the element to govern translational efficiency.

Active Grant Support

• Principal Investigator: "Translational Control of Breast Cancer" NIH/NCI RO1, CA-11338, 2005-2010

Selected Recent Publications

Ghosh P, Park C, Peterson M, Bitterman P, Polunovsky V, Wagner C. Synthesis and evaluation of eIF4E cap binding to 7-methyl GTP. Bioorganic Med Chem Let, 15: 2177-2180, 2005.

Jacobson BA, Alter MD, Kratzke MG, Frizelle SP, Zhang Y, Peterson MS, Avdulov S, Mohorn R, Whitson BA, Bitterman PB, Polunovsky VA, Kratzke RA. Repression of cap-dependent translation attenuates the transformed phenotype in non-small cell lung cancer both in vivo and in vitro. Cancer Res.  66: 4256-4262, 2006.

Larsson O, Perlman D, Fan D, Reilly C, Peterson M., Dahlgren C, Liang Z, Li S, Polunovsky V, Wahlestedt C, and Bitterman P.  Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure.  Nucleic Acid Res, 34: 4375-4386, 2006.

Polunovsky VA and Bitterman PB. The cap-dependent translational apparatus integrates and amplifies cancer pathways. RNA Biology, 3:10-17, 2006.

Larsson O, Li S, Issaenko OS, Avdulov S, Peterson M, Smith K, Bitterman PB, Polunovsky VA.  eIF4E-induced progression of primary HMECs along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors.  Cancer Res,  2007; 67(14): 6814-24.

Ghosh P, Cheng J, Chou TF, Jia Y, Avdulov S, Bitterman PB, Polunovsky VA, Wagner CR. Expression, purification and characterization of recombinant mouse translation initiation factor eIF4E as a dihydrofolate reductase (DHFR) fusion protein. Protein Expr Purif, 2008; 60(2):132-9.

Ghosh B, Benyumov AO, Ghosh P, Jia Y, Avdulov S, Dahlberg PS, Peterson M, Smith K, Polunovsky VA, Bitterman PB, Wagner CR. Nontoxic chemical interdiction of the epithelial-to-mesenchymal transition by targeting cap-dependent translation. ACS Chem Biol. 2009; 4(5):367-77.

Kim YY, Von Weymarn L, Larsson O, Fan D, Underwood JM, Peterson MS, Hecht SS, Polunovsky VA, Bitterman PB.  Eukaryotic initiation factor 4E-binding protein family of proteins: sentinels at a translational control checkpoint in lung tumor defense.  Cancer Res. 2009;69(21):8455-62.