Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells

Natalia I. Díaz-Valdivia, Claudia C. Calderón, Jorge E. Díaz, Lorena Lobos-González, Hugo Sepulveda, Rina J. Ortíz, Samuel Martinez, Veronica Silva, Horacio J. Maldonado, Patricio Silva, Sergio Wehinger, Verónica A. Burzio, Vicente A. Torres, Martín Montecino, Lisette Leyton, Andrew F.G. Quest

Resultado de la investigación: Article

2 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)111943-111965
Número de páginas23
PublicaciónOncotarget
Volumen8
N.º67
DOI
EstadoPublished - 1 ene 2017

Huella dactilar

Caveolin 1
Neoplasm Metastasis
Pharmaceutical Preparations
Neoplasms
Epigenomics
Colonic Neoplasms
Azacitidine
src-Family Kinases
Mitogen-Activated Protein Kinase Kinases
Methyltransferases
Drug Resistance
Molecular Biology
Breast Neoplasms
Drug Therapy

ASJC Scopus subject areas

  • Oncology

Citar esto

Díaz-Valdivia, N. I., Calderón, C. C., Díaz, J. E., Lobos-González, L., Sepulveda, H., Ortíz, R. J., ... Quest, A. F. G. (2017). Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells. Oncotarget, 8(67), 111943-111965. https://doi.org/10.18632/oncotarget.22955
Díaz-Valdivia, Natalia I. ; Calderón, Claudia C. ; Díaz, Jorge E. ; Lobos-González, Lorena ; Sepulveda, Hugo ; Ortíz, Rina J. ; Martinez, Samuel ; Silva, Veronica ; Maldonado, Horacio J. ; Silva, Patricio ; Wehinger, Sergio ; Burzio, Verónica A. ; Torres, Vicente A. ; Montecino, Martín ; Leyton, Lisette ; Quest, Andrew F.G. / Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells. En: Oncotarget. 2017 ; Vol. 8, N.º 67. pp. 111943-111965.
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title = "Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells",
abstract = "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.",
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Díaz-Valdivia, NI, Calderón, CC, Díaz, JE, Lobos-González, L, Sepulveda, H, Ortíz, RJ, Martinez, S, Silva, V, Maldonado, HJ, Silva, P, Wehinger, S, Burzio, VA, Torres, VA, Montecino, M, Leyton, L & Quest, AFG 2017, 'Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells', Oncotarget, vol. 8, n.º 67, pp. 111943-111965. https://doi.org/10.18632/oncotarget.22955

Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells. / Díaz-Valdivia, Natalia I.; Calderón, Claudia C.; Díaz, Jorge E.; Lobos-González, Lorena; Sepulveda, Hugo; Ortíz, Rina J.; Martinez, Samuel; Silva, Veronica; Maldonado, Horacio J.; Silva, Patricio; Wehinger, Sergio; Burzio, Verónica A.; Torres, Vicente A.; Montecino, Martín; Leyton, Lisette; Quest, Andrew F.G.

En: Oncotarget, Vol. 8, N.º 67, 01.01.2017, p. 111943-111965.

Resultado de la investigación: Article

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.

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

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U2 - 10.18632/oncotarget.22955

DO - 10.18632/oncotarget.22955

M3 - Article

VL - 8

SP - 111943

EP - 111965

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 67

ER -

Díaz-Valdivia NI, Calderón CC, Díaz JE, Lobos-González L, Sepulveda H, Ortíz RJ y otros. Anti-neoplastic drugs increase caveolin-1-dependent migration, invasion and metastasis of cancer cells. Oncotarget. 2017 ene 1;8(67):111943-111965. https://doi.org/10.18632/oncotarget.22955