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  • Review Article
  • Published:

Validating survivin as a cancer therapeutic target

Nature Reviews Cancer volume 3, pages 46–54 (2003)Cite this article

Key Points

  • In mammalian cells, apoptosis is modulated by two protein families — the BCL2 and inhibitor of apoptosis (IAP) families.

  • Survivin is a unique member of the IAP family. It is associated with several subcellular compartments and its expression is regulated by many signalling pathways.

  • The survivin pathway interfaces with both the cell-death machinery and mechanisms of cell-cycle progression and microtubule stability.

  • Survivin expression is undetectable in most normal adult tissues, but is overexpressed in virtually every human tumour that has been studied. Several mechanisms have been proposed to account for this overexpression, one of which is loss of wild-type p53.

  • Is survivin a rational target for cancer therapy? Using molecular antagonists of survivin is one approach for enhancing cell death — specifically of tumours — and could be used in combination with conventional chemotherapy- or radiation-based treatments.

Abstract

Acquisition of the ability to evade cellular suicide, or apoptosis, is one of the master switches that contributes to cellular transformation and, ultimately, to invasive cancer. Much has been learned about the molecular organization of apoptotic pathways and their regulators, but the identification and validation of translational targets for apoptosis-based cancer therapy has posed a great challenge. Survivin is an attractive candidate for cancer therapy, so what is its potential applicability in the clinic?

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Figure 1: Apoptotic pathways and their regulators.
Figure 2: Structure–function of survivin proteins generated by alternative splicing.
Figure 3: Differential regulation of survivin expression in cell-cycle-dependent and -independent pathways.
Figure 4: Expression of survivin in tumours is independent of the mitotic index.
Figure 5: Current approaches for survivin targeting in cancer therapy.

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Acknowledgements

This work was supported by National Institute of Health grants. The expert editorial assistance of K. Lougie is greatly appreciated.

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Authors and Affiliations

  1. Department of Cancer Biology, LRB-428, University of Massachusetts Medical School, 364 Plantation Street, Worcester, 01605, Massachusetts, USA

    Dario C. Altieri

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  1. Dario C. Altieri
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DATABASES

LocusLink

BAD

BAK

BAX

BCL2

BCL-XL

BID

β-catenin

CDC2

cyclin B1

cyclin D

DIAP1

FAS

c-IAP1

c-IAP2

LATS1

OMI

p53

SMAC

STAT3

survivin

TNF-α

VEGF

WAF1

XIAP

Glossary

RING FINGER

A protein domain that consists of two loops held together at their base by cysteine and histidine residues that complex two zinc ions. Many ring fingers function in protein degradation by facilitating protein ubiquitylation.

TGF-β

A ligand that activates members of a superfamily of cell-surface receptors that include the bone morphogenic protein (BMP) receptors; after ligand activation, the signal is transduced, mainly through the SMAD family of transcription factors and co-activators.

JNK

(c-JUN amino-terminal kinase). A stress-induced protein kinase that has been implicated in cell death or cell viability, depending on the cellular context, and is activated by XIAP.

Ki67

A monoclonal antibody that marks the late S phase of the cell cycle. This is frequently used to mark proliferating cells in tissues or cell suspensions.

PI3K/AKT PATHWAY

The phosphatidylinositol 3-kinase (PI3K) family of enzymes are activated in response to a wide variety of stimuli and catalyse the phophorylation of inositol lipids at the D-3 position of the inositol ring. These phosphoinositides act as second messengers; a primary target is the serine/threonine kinase AKT (protein kinase B). Activated AKT phosphorylates several cellular targets, including proteins that are involved in cell survival, proliferation and migration.

STAT3

A member of the STAT (signal transducer and activator of transcription) family of transcription factors. STATs are activated through phosphorylation by Janus kinases and have an important role in cytokine-receptor signalling.

ANTISENSE TECHNOLOGY

This uses an oligonucleotide that is complementary to a portion of mRNA. It binds to the mRNA and arrests translation by physical blockade of ribosomal machinery and/or by activation of endogenous RNases.

RIBOZYMES

RNA molecules that function like enzymes and exert a catalytic activity. Ribozymes can be designed to cleave specific mRNAs and thereby inhibit protein synthesis.

DOMINANT-NEGATIVE MUTANTS

A non-functional mutant protein that competes with the normal, non-mutated protein, thereby blocking its activity.

TRANSCRIPTOME

mRNA transcripts identified by serial analysis of gene expression (SAGE) that are selectively expressed in human tumours but undetectable or found at very low levels in normal tissues that are isolated from the same organs.

WNT–β-CATENIN SIGNALLING PATHWAY

A developmental pathway of key importance for patterning and specification of body axes in embryogenesis via activation of genes that are mediated by the T-cell factor (TCF) group of transcription factors. Deregulated signalling through Wnt/TCF/β-catenin has been implicated in a variety of human tumours, most notably colon cancer, potentially by deregulating the balance between cell proliferation/cell differentiation in stem-cell compartments.

APC

Germ-line mutations of the adenomatous polyposis coli (APC) tumour-suppressor gene cause familial adenomatous polyposis — a genetic disorder that is characterized by an increased predisposition to colorectal cancer.

CYTOLYTIC RESPONSE

Destruction of cellular targets by T lymphocytes via a perforin–granzyme mechanism or FAS–FAS-ligand interaction, leading to the dissolution of membrane integrity.

HLA CLASS I-RESTRICTED CYTOLYTIC T CELLS

Antigen-specific T cells recognizing peptides presented through the HLA class I major histocompatibility complex are capable of lysing compatible target cells. These cells might belong to the CD4 or CD8 subset and are believed to act in immune surveillance against tumours.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

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Altieri, D. Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3, 46–54 (2003). https://doi.org/10.1038/nrc968

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  • DOI: https://doi.org/10.1038/nrc968

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