RESUMO
The adenomatous polyposis coli (APC) protein is crucial to homeostasis of normal intestinal epithelia because it suppresses the ß-catenin/TCF pathway. Consequently, loss or mutation of the APC gene causes colorectal tumors in humans and mice. Here, we describe our use of multidimensional protein identification technology (MudPIT) to compare protein expression in colon tumors to that of adjacent healthy colon tissue from Apc(Min/+) mice. Twenty-seven proteins were found to be up-regulated in colon tumors and 25 were down-regulated. As an extension of the proteomic analysis, the differentially expressed proteins were used as "seeds" to search for coexpressed genes. This approach revealed a coexpression network of 45 genes that is up-regulated in colon tumors. Members of the network include the antibacterial peptide cathelicidin (CAMP), Toll-like receptors (TLRs), IL-8, and triggering receptor expressed on myeloid cells 1 (TREM1). The coexpression network is associated with innate immunity and inflammation, and there is significant concordance between its connectivity in humans versus mice (Friedman: p value = 0.0056). This study provides new insights into the proteins and networks that are likely to drive the onset and progression of colon cancer.
Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Neoplasias do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Imunidade Inata/genética , Proteômica/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/metabolismo , Neoplasias do Colo/imunologia , Biologia Computacional , Primers do DNA/genética , Perfilação da Expressão Gênica , Humanos , Interleucina-8/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Mutantes , Receptores Imunológicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrofotometria , Receptores Toll-Like/metabolismo , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
PURPOSE: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds. EXPERIMENTAL DESIGN: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. RESULTS: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. CONCLUSION: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.