BBA - Reviews on Cancer (v.1755, #1)

A survey of alternative transcripts of human tissue kallikrein genes by Lisa Kurlender; Carla Borgono; Iacovos P. Michael; Christina Obiezu; Marc B. Elliott; George M. Yousef; Eleftherios P. Diamandis (1-14).
Alternative splicing is prevalent within the human tissue kallikrein gene locus. Aside from being the most important source of protein diversity in eukaryotes, this process plays a significant role in development, physiology and disease. A better understanding of alternative splicing could lead to the use of gene variants as drug targets, therapeutic agents or diagnostic markers. With the rapidly rising number of alternative kallikrein transcripts, classifying new transcripts and piecing together the significance of existing data are becoming increasingly challenging. In this review, we present a systematic analysis of all currently known kallikrein alternative transcripts. By defining a reference form for each of the 15 kallikrein genes (KLK1 to KLK15), we were able to classify alternative splicing patterns. We identified 82 different kallikrein gene transcript forms, including reference forms. Alternative splicing may lead to the synthesis of 56 different protein forms for KLK1-15. In the kallikrein locus, the majority of alternative splicing events occur within the protein-coding region, and to a lesser extent in the 5′ untranslated regions (UTRs). The most common alternative splicing event is exon skipping (35%) and the least common events are cryptic exons (3%) and internal exon deletion (3%). Seventy-six percent of kallikrein splice variants that are predicted to encode truncated proteins are the result of frameshifts. Eighty-nine percent of putative proteins encoded by splice variants are predicted to be secreted. Although several reports describe the identification of kallikrein splice variants and their potential clinical utility, this is the first extensive review on this subject. Accumulating evidence suggests that alternative kallikrein forms could be involved in many pathologic conditions or could have practical applications as biomarkers. The organization and analysis of the kallikrein transcripts will facilitate future work in this area and may lead to novel clinical and diagnostic applications.
Keywords: Kallikrein; Alternative splicing; Differential expression; Serine protease; Splice variant; Cancer biomarker;

Direct oxidative DNA damage, apoptosis and radio sensitivity by spermine oxidase activities in mouse neuroblastoma cells by R. Amendola; A. Bellini; M. Cervelli; P. Degan; L. Marcocci; F. Martini; P. Mariottini (15-24).
In mammals, the polyamines affect cell growth, differentiation, and apoptosis; their levels are increased in malignant and proliferating cells, thus justifying an interest in a chemotherapeutic approach to cancer. The flavoprotein SMO is the most recently characterized catabolic enzyme, preferentially oxidizing SPM to SPD, 3-aminopropanal and H2O2. In this report, we describe a novel functional characterization of the recently cloned splice variant isoforms from mouse brain, encoding, among others, the nuclear co-localized spermine oxidase mSMOμ. The over-expression of the active isoforms mSMOα and mSMOμ, and the inactive mSMOδ and mSMOγ in mouse neuroblastoma cells, demonstrated the first evidence of the direct oxidative DNA damage by the SMO activities, either alone or, in a higher extent, when associated with radiation exposure, thus working as radio sensitizer. These effects were reverted by treatment with 50 μM and 100 μM doses of the inhibitor of SMO activity MDL 72,527. The over-expression of all SMO isoforms failed to influence the expression of the regulating enzymes of polyamines metabolism ODC and SSAT. Dealing with the unbalanced tissue specific SMO activities, these results could indicate a new direction to tailor chemotherapy-associated radiotherapy, improving dose-rate protocol and allowing the modulation of deleterious side effects on healthy tissues.
Keywords: Apoptosis; DNA damage; Neuroblastoma; Oxidative stress; Polyamine; Radiation;

Does CD95 have tumor promoting activities? by Marcus E. Peter; Patrick Legembre; Bryan C. Barnhart (25-36).
CD95 (APO-1/Fas) is an important inducer of the extrinsic apoptosis signaling pathway and therapy induced apoptosis of many tumor cells has been linked to the activity of CD95. Changes in the expression of CD95 and/or its ligand CD95L are frequently found in human cancer. The downregulation or mutation of CD95 has been proposed as a mechanism by which cancer cells avoid destruction by the immune system through reduced apoptosis sensitivity. CD95 has therefore been viewed as a tumor suppressor. Furthermore, increased CD95L concentration in tumor patients has been linked to tumor cells killing infiltrating lymphocytes in a process called “the tumor counter attack”. Recent data have illuminated unknown activities of CD95 in tumor cells with downregulated or mutated CD95 in the presence of increased CD95L. Under these conditions the stimulation of CD95 signals nonapoptotic pathways, activating NF-κB and MAP kinases for example, which may result in the induction of tumorigenic or prosurvival genes. A new model of CD95 functions is proposed in which CD95 is converted from a tumor suppressor to a tumor promotor by a single point mutation in one of the CD95 alleles, a situation frequently found in advanced human cancer, resulting in apoptosis resistance and activation of tumorigenic pathways.

Gelatinase-mediated migration and invasion of cancer cells by Mikael Björklund; Erkki Koivunen (37-69).
The matrix metalloproteinases(MMP)-2 and -9, also known as the gelatinases have been long recognized as major contributors to the proteolytic degradation of extracellular matrix during tumor invasion. In the recent years, a plethora of non-matrix proteins have also been identified as gelatinase substrates thus significantly broadening our understanding of these enzymes as proteolytic executors and regulators in various physiological and pathological states including embryonic growth and development, angiogenesis and tumor progression, inflammation, infective diseases, degenerative diseases of the brain and vascular diseases. Although the effect of broad-spectrum inhibitors of MMPs in the treatment of cancer has been disappointing in clinical trials, novel mechanisms of gelatinase inhibition have been now identified. Inhibition of the association of the gelatinases with cell-surface integrins appears to offer highly specific means to target these enzymes without inhibiting their catalytic activity in multiple cell types including endothelial cells, tumor cells and leukocytes. Here, we review the multiple functions of the gelatinases in cancer, and especially their role in the tumor cell migration and invasion.