Despite intensive research, many cancer treatment strategies present unsuccessful. This is reflected in colorectal cancer (CRC) as the second leading cause of cancer associated deaths worldwide. Here, the development of distant metastasis represents a major challenge in therapy. In addition, reliable and efficient biomarkers for early prognosis of disease course or selection of patients for specific treatment (prediction) remain scarce. Metastasis-associated in colon cancer 1 (MACC1) has been established as prognostic, predictive and causal biomarker for several tumor entities. It has been found to induce different target genes such as MET, NANOG and SPON2 and affect several signaling pathways including MEK/ERK and AKT/β-catenin. Thus, it promotes cell proliferation, migration and colony formation as well as tumor progression and metastasis formation in vivo. This study intended to explore new strategies to inhibit these processes by targeting MACC1.
We employed two distinct screening methods to find novel, more potent transcriptional inhibitors of MACC1 and illuminate the MACC1 signaling landscape to uncover new drug intervention points. With the first screening and subsequent validation, nearly all clinically employed statins were revealed as potent MACC1 transcriptional inhibitors. Chosen as strongest inhibitors, Fluvastatin and Atorvastatin showed MACC1-specific reduction ofproliferation and colony formation in vitro as well as restriction of tumor growth and metastasis formation in vivo at doses equivalent to human standard lipid reduction therapy. Moreover, we identified phosphotyrosine (pY)-dependent interactions of MACC1 with crucial signaling molecules: SHP2, GRB2, SHC1, PLCG1 and STAT5B. Mutation of the interaction sites abrogated MACC1-dependent ERK signaling as well as cell migration and proliferation. Our data further suggest that MACC1 governs SHP2/SRC/ERK and PKA/SRC/CREB axes conferring a malignant phenotype in response to different receptor tyrosine kinases such as MET and EGFR. Targeted intervention with inhibitors of MET, MEK, SHP2 and SRC restricted MACC1-dependent colony formation. These results indicate new drug intervention points for MACC1 signaling and provide an excellent baseline for further investigations of combinatorial treatments with other targeted inhibitors (e.g. GRB2, PKA), potential MACC1 pY-antibodies or statins.
Additional research about the spatiotemporal organization of MACC1 signalosome formation and downstream signaling, particularly in vivo, will reveal the entire potential of MACC1 as therapeutic target, whereas statins should already be considered for cancer therapy or prevention, especially in patients stratified for MACC1 expression.
|Advisor:||Stein , Ulrike , Klipp , Edda , Feller , Stephan Michael|
|School:||Humboldt Universitaet zu Berlin (Germany)|
|Source:||DAI-C 81/8(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Oncology|
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