The natural tumor suppressor protein maspin and potential application in non small cell lung cancer

Abstract

The grim prognosis of lung cancer, that has an overall 10-15% survival at 5 years, remains in the US the leading cause of cancer mortality, provides a compelling rationale for studying the molecular basis of this malignancy. Surmising the common, general association with smoking, lung cancers differ at the microscopic, anatomical, epidemiological and clinical level and harbor complex genetic and epigenetic alterations. Currently, lung cancer is divided into small cell lung carcinoma (SCLC) and non small cell lung carcinoma (NSCLC) for the purpose of clinical management. (NSCLC) constitutes 80-85% of lung cancers and is further divided into histological subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, etc. The ultimate goal for lung cancer research is to develop a strategy to block the tumor progression and improve the prognosis of lung cancer. This goal can realistically be achieved only when the biological complexity of this disease is taken into account. To this end, identification and understanding of molecular markers that are mechanistically involved in tumor progression is needed. Our recent studies suggest histological subtype-dependent distinct correlations between the expression and/or subcellular localization of tumor suppressive maspin with the progression and prognosis of NSCLC. Maspin is an epithelial specific member of the serine protease inhibitor (serpin) superfamily but recently identified as an endogenous inhibitor of histone deacetylase 1 (HDAC1). This novel biochemical activity coincides with a consensus emerged recently from the evidence that nuclear maspin confers better differentiated epithelial phenotypes, decreased tumor angiogenesis, increased tumor sensitivity to drug-induced apoptosis, and a more favorable prognosis. In the current review, we discuss the evidence that maspin may be a marker that stratifies the progression and prognosis of different subtypes of NSCLC.

Fig. 1. The Possible Mode of Molecular Interaction of Maspin and HDAC1

Surface representations of maspin and HDAC1, colored according to electrostatic potential. A. Crystal structure of maspin. Arg-340 is shown in stick representation. B. Model of HDAC1 structure produced basing on crystal structure of HDAC8. Catalytic triad residues are shown in stick representation and Zn²⁺ ion as magenta sphere. C. Slice of the molecular surface of HDAC1 active site shows the feasibility for maspin RSL to fit into the catalytic domain of HDAC1. View is rotated approximately 90° about the vertical axis of B.

Fig. 2

The Substrate Acetylated Lysine as A Template for Synthetic HDAC inhibitors.