Structural, functional and therapeutic biology of survivin

Abstract

Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family that interferes with post-mitochondrial events including activation of caspases. Survivin regulates cell cycle also. It is expressed in most of the human tumors, but it is barely detectable in the terminally differentiated normal cells/tissues. Molecular mechanisms of regulation of survivin in cancer are not clearly understood. Nevertheless, the functional loss of wild type p53 is often associated with upregulation of survivin. Tumors that over-express survivin generally bear a poor prognosis and are associated with resistance to therapy. The differential expression of survivin in cancer versus normal tissues makes it a useful tool in cancer diagnosis and a promising therapeutic target. A growing body of literature suggests nuclear expression of survivin as a good prognostic marker. Disruption of the survivin induction pathway has resulted in an increase in apoptosis and inhibition of tumor growth. Regular therapies, such as, radiotherapy in combination with anticancer drugs in clinical practice may yield promising results.

Introduction

Survivin belongs to a family of proteins, known as inhibitor of apoptosis protein (IAP), which plays a key role in the regulation of apoptosis and cell division [1], [2]. It is characterized by the presence of single BIR repeat and lacks carboxyl terminal RING finger domain in its protein structure [3], [4], [5]. Survivin is abundantly expressed in the embryonic tissues and in most of the tumors, but in the normal differentiated cells it is almost absent [5]. Survivin is expressed in the G2/M phase of the cell cycle to support the rapidly-dividing cell machinery [1], [5]. It helps proper segregation of chromosomes during cell division [6], [7]. Over expression of survivin in cancer may overcome cell cycle checkpoints to facilitate aberrant progression of transformed cells through mitosis.

Research work on the apoptotic cell death pathways provides good means for the discovery and development of novel drugs to cure cancer. Many drugs kill tumor cells by inducing apoptosis; but some tumors show resistance against these agents. One of the important factors that provide potent resistance against chemotherapeutic drugs is evidently survivin [8]. Several studies have demonstrated resistance of survivin-expressing cells to anticancer drug-induced apoptosis [9], [10]. For example, treatment with survivin-antisense potently sensitized tumor cells to apoptosis by chemotherapy and radiation [11], [12]. Exploitation of survivin signaling pathway may thus provide important predictive and prognostic clues to cancer diagnosis and may also offer new therapeutic alternatives for cancer treatment [13], [14].