Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers.
To identify genes that could serve as targets for novel cancer therapeutics, we used a bioinformatic analysis of microarray data comparing gene expression between normal and tumor-derived primary human tissues. From this approach, we have found that maternal embryonic leucine zipper kinase (Melk), a member of the AMP serine/threonine kinase family, exhibits multiple features consistent with the potential utility of this gene as an anticancer target. An oligonucleotide microarray analysis of multiple human tumor samples and cell lines suggests that Melk expression is frequently elevated in cancer relative to normal tissues, a pattern confirmed by quantitative reverse transcription-PCR and Western blotting of selected primary tumor samples. In situ hybridization localized Melk expression to malignant epithelial cells in 96%, 23%, and 13% of colorectal, lung, and ovarian tissue tumor samples, respectively. Expression of this gene is also elevated in spontaneous tumors derived from the ApcMin and Apc1638N murine models of intestinal tumorigenesis. To begin addressing whether Melk is relevant for tumorigenesis, RNA interference-mediated silencing within human and murine tumor cell lines was done. We show that Melk knockdown decreases proliferation and anchorage-independent growth in vitro as well as tumor growth in a xenograft model. Together, these results suggest that Melk may provide a growth advantage for neoplastic cells and, therefore, inactivation may be therapeutically beneficial.
Gray
Daniel
D
Department of Molecular Biology, Pathology, and Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA.
Jubb
Adrian M
AM
Hogue
Deborah
D
Dowd
Patrick
P
Kljavin
Noelyn
N
Yi
Sothy
S
Bai
Wei
W
Frantz
Gretchen
G
Zhang
Zemin
Z
Koeppen
Hartmut
H
de Sauvage
Frederic J
FJ
Davis
David P
DP
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology; D006367:HeLa Cells; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases