Survivin, a molecular target for therapeutic interventions in squamous cell carcinoma

Abstract

Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.

Keywords: Apoptosis; CDK inhibitors; Cancer immunotherapy; Hsp90 inhibitors; Squamous cell carcinoma (SCC); Survivin; YM155.

Fig. 1

Role of survivin in cell cycle. In association with Aurora B and ICP, survivin forms a chromosomal passenger complex that bind to their target sites including centromere, midplate and cleavage furrow, where it regulates proper chromosome segregation and cytogenesis

Fig. 2

Role of survivin in apoptosis. Apoptosis can be initiated by the death-receptor (extrinsic) pathway or mitochondrial (intrinsic) pathway. Extrinsic pathway acts through caspase-8 and intrinsic pathway acts through caspase-9, but both pathways converge to activate the effector caspases-3,-7. Survivin largely interferes in mitochondrial-mediated apoptotic pathway. Apoptosome complex formed in association of Cyt-c, Apaf-1 and procaspase-9 in presence of dATP that leads to activation of procaspase-9. Survivin most probably blocks activation of caspase-9 by inhibiting apoptosome formation. It may also inhibit initiator caspase-9 and effector caspases-3 directly. Smac/DIABLO is a proapoptotic protein that inhibits activity of IAPs. Survivin antagonize the activity of Smac/DIABLO and may help in the action of another IAPs such as XIAP. XIAP is a strong inhibitor of apoptosis, which interacts directly with caspases and inhibits them

Fig. 3

Schematic representation of different techniques to target survivin for therapeutic purposes. a Antisense technology, such as antisense oligonucleotides, siRNA and shRNA target survivin mRNA to inhibit translation. b Ribozyme is also an advanced antisense method to target mRNA. The specificity of ribozyme determined by the paired regions flanking the cleavage site. c Dimerization and phosphorylation on Thr34 residue is essential for survivin activation and Hsp90 provide stability to survivin dimer. Small molecule antagonists for survivin activation, such as CDK and Hsp90 inhibitors, able to inhibit survivin phosphorylation or its interaction with Hsp90, consequently inhibit survivin functions. d In dominant negative mutants, an essential amino acid of the survivin is replaced by another amino acid that leads to the loss of function. For example, Thr34Ala mutant inhibit survivin activation through abolishing phosphorylation of Thr34 residue, and Cys84Ala mutant inhibit survivin dimerization. e Survivin-directed immunotherapy approaches. Peptides-derived from survivin can induce CTL activity against tumor cells