Expression of the scaffolding
protein Caveolin-1 (CAV1) enhances migration and invasion of metastatic
cancer cells. Yet, CAV1 also functions as a
tumor suppressor in early stages of
cancer, where expression is suppressed by epigenetic mechanisms. Thus, we sought to identify stimuli/mechanisms that revert epigenetic CAV1 silencing in
cancer cells and evaluate how this affects their metastatic potential. We reasoned that restricted tissue availability of anti-neoplastic drugs during
chemotherapy might expose
cancer cells to sub-therapeutic concentrations, which activate signaling pathways and the expression of CAV1 to favor the acquisition of more aggressive traits. Here, we used in vitro [2D, invasion] and in vivo (
metastasis) assays, as well as genetic and biochemical approaches to address this question. Colon and
breast cancer cells were identified where CAV1 levels were low due to epigenetic suppression and could be reverted by treatment with the
methyltransferase inhibitor 5'-azacytidine. Exposure of these cells to anti-neoplastic drugs for short periods of time (24-48 h) increased CAV1 expression through ROS production and
MEK/ERK activation. In
colon cancer cells, increased CAV1 expression enhanced migration and invasion in vitro via pathways requiring
Src-family kinases, as well as Rac-1 activity. Finally, elevated CAV1 expression in
colon cancer cells following exposure in vitro to sub-cytotoxic drug concentrations increased their metastatic potential in vivo. Therefore exposure of
cancer cells to anti-neoplastic drugs at non-lethal drug concentrations induces signaling events and changes in transcription that favor CAV1-dependent migration, invasion and
metastasis. Importantly, this may occur in the absence of selection for drug-resistance.