Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling

• Published in: PloS one Vol. 13; no. 4; p. e0195401
• Main Authors: Luchsinger, Charlotte, Aguilar, Marcelo, Burgos, Patricia V, Ehrenfeld, Pamela, Mardones, Gonzalo A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.04.2018; Public Library of Science (PLoS)
• Subjects: Actinomycin; AKT protein; Analysis; Apoptosis; Biology; Biology and Life Sciences; Biosynthesis; Breast cancer; Brefeldin A; Cancer; Cancer cells; Cancer therapies; Cell adhesion & migration; Cell growth; Cell migration; Cell proliferation; Cellular signal transduction; Chemotherapy; Combined treatment; Dactinomycin; Dosage and administration; Drug therapy; Drugs; Extracellular signal-regulated kinase; Genetic aspects; Golgi apparatus; Golgi cells; Homeostasis; Interdisciplinary aspects; Kinases; Medical research; Medicine; Medicine and Health Sciences; Nervous system; Physiology; Protein biosynthesis; Proteins; Research and Analysis Methods; Sensitivity; Sensitivity analysis; Signal transduction; Signaling; Transformation; Vinblastine; Chile
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0195401

Increasing evidence indicates that the Golgi apparatus plays active roles in cancer, but a comprehensive understanding of its functions in the oncogenic transformation has not yet emerged. At the same time, the Golgi is becoming well recognized as a hub that integrates its functions of protein and lipid biosynthesis to signal transduction for cell proliferation and migration in cancer cells. Nevertheless, the active function of the Golgi apparatus in cancer cells has not been fully evaluated as a target for combined treatment. Here, we analyzed the effect of perturbing the Golgi apparatus on the sensitivity of the MDA-MB-231 breast cancer cell line to the drugs Actinomycin D and Vinblastine. We disrupted the function of ARF1, a protein necessary for the homeostasis of the Golgi apparatus. We found that the expression of the ARF1-Q71L mutant increased the sensitivity of MDA-MB-231 cells to both Actinomycin D and Vinblastine, resulting in decreased cell proliferation and cell migration, as well as in increased apoptosis. Likewise, the combined treatment of cells with Actinomycin D or Vinblastine and Brefeldin A or Golgicide A, two disrupting agents of the ARF1 function, resulted in similar effects on cell proliferation, cell migration and apoptosis. Interestingly, each combined treatment had distinct effects on ERK1/2 and AKT signaling, as indicated by the decreased levels of either phospho-ERK1/2 or phospho-AKT. Our results suggest that disruption of Golgi function could be used as a strategy for the sensitization of cancer cells to chemotherapy.