Metastatic
prostate cancer continues to pose a difficult therapeutic challenge.
Prostate cancer progression is associated with aberrant O-glycosylation of
cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous
metastasis of human
prostate cancer xenografts that express high levels of
galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation.
Galectin-4 expression in clinical specimens of
prostate cancer correlated with poor patient survival.
Galectin-4 binding to multiple
receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt,
fibronectin, and Twist1, and lowered expression of
E-cadherin, thereby facilitating epithelial-mesenchymal transition, invasion, and
metastasis. In vivo investigations established that
galectin-4 expression enabled
prostate cancer cells to repopulate
tumors in orthotopic and
heterotopic tissues. Notably, these effects of
galectin-4 relied upon O-glycosylation mediated by C1GALT1, a
galactosyltransferase implicated in other
cancers. Parallel changes in
galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in
prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal
tumors. Our findings establish
galectin-4 and C1GALT1-mediated glycosylation in a signaling axis that is activated during
prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease.
Cancer Res; 76(19); 5756-67. ©2016 AACR.