CD44 expressed in
cancer cells was shown to stabilize
cystine transporter (xCT) that uptakes
cystine and excretes
glutamate to supply
cysteine as a substrate for
reduced glutathione (GSH) for survival. While targeting CD44 serves as a potentially therapeutic stratagem to attack
cancer growth and chemoresistance, the impact of CD44 targeting in
cancer cells on metabolic systems of
tumors and host tissues in vivo remains to be fully determined. This study aimed to reveal effects of CD44 silencing on alterations in energy metabolism and
sulfur-containing metabolites in vitro and in vivo using capillary electrophoresis-mass spectrometry and quantitative imaging mass spectrometry (Q-IMS), respectively. In an experimental model of
xenograft transplantation of human
colon cancer HCT116 cells in superimmunodeficient NOG mice, snap-frozen liver tissues containing metastatic
tumors were examined by Q-IMS. As reported previously, short hairpin CD44 RNA interference (shCD44) in
cancer cells caused significant regression of
tumor growth in the host liver. Under these circumstances, the CD44 knockdown suppressed
polyamines, GSH and energy charges not only in metastatic
tumors but also in the host liver. In culture, HCT116 cells treated with shCD44 decreased total amounts of
methionine-pool metabolites including
spermidine and
spermine, and reactive
cysteine persulfides, suggesting roles of these metabolites for
cancer growth. Collectively, these results suggest that CD44 expressed in
cancer accounts for a key regulator of metabolic interplay between
tumor and the host tissue.