Targeting
metabolic enzymes in
human cancer Abstract
Lung cancer is a devastating
disease and a major therapeutic burden with
poor prognosis. The functional heterogeneity of
lung cancer (different
tumor formation ability in bulk of tumor) is highly related with clinical chemoresistance and relapse. Here we find that,
glycine dehydrogenase (GLDC), one of the metabolic
enzyme involved in
glycine metabolism, is overexpressed in various subtypes of
human lung cancer and possibly several other types of cancers. GLDC was found to be highly expressed in tumor-initiating subpopulation of
human lung cancer cells compared with non-tumorigenic subpopulation. By array studies we showed that
normal lung cells express low levels of GLDC compared to xenograft and
primary tumor.
Functional studies showed that RNAi inhibition of GLDC inhibits significantly the clonal growth of tumor-initiating cells
in vitro and
tumor formation in immunodeficient mice. Overexpression of GLDC in non-tumorigenic subpopulation convert the cells to become tumorigenic. Furthermore, over-expression of GLDC in NIH / 3T3 cells and human primary
lung fibroblasts can transform these cells, displaying anchorage-independent growth in
soft agar and tumor-forming in mice. Not only is GLDC is expressed
human lung cancer, it is also up-regulated in other types of cancer, such as colon cancer. RNAi knockdown of GLDC in
colon cancer cell line, CACO-2 cells, can also inhibit the
tumor formation in mice. Thus GLDC maybe a new metabolic target for
treatment of lung cancer, and other cancers.