TY - JOUR
T1 - Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells
AU - Díaz-Valdivia, Natalia I.
AU - Calderón, Claudia C.
AU - Díaz, Jorge E.
AU - Lobos-González, Lorena
AU - Sepulveda, Hugo
AU - Ortíz, Rina J.
AU - Martinez, Samuel
AU - Silva, Veronica
AU - Maldonado, Horacio J.
AU - Silva, Patricio
AU - Wehinger, Sergio
AU - Burzio, Verónica A.
AU - Torres, Vicente A.
AU - Montecino, Martín
AU - Leyton, Lisette
AU - Quest, Andrew F.G.
N1 - Funding Information:
This work was supported by CONICYT-FONDAP 15130011 (AFGQ), FONDECYT 1130250, 1170925 (AFGQ), Anillo ACT 1111 (AFGQ), CONICYT-FONDAP 15090007 (MM), FONDECYT 1150744 (LL), FONDECYT 1140907 (VAT), and CONICYT PhD fellowships (NDV, RO, JD, HM, PS), FONDECYT 11140204 (LLG), BASAL CCTE-PFB16 CONICYT (LLG, VB).
Publisher Copyright:
© Díaz-Valdivia et al.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Caveolin-1
KW - Cell signaling
KW - Chemotherapy
KW - Epigenetic silencing
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85038422813&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.22955
DO - 10.18632/oncotarget.22955
M3 - Article
AN - SCOPUS:85038422813
SN - 1949-2553
VL - 8
SP - 111943
EP - 111965
JO - Oncotarget
JF - Oncotarget
IS - 67
ER -