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

Abstract

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.

E-cadherin endocytosis is modulated by p120-catenin through the opposing actions of RhoA and Arf1

“…No surviving larvae were observed, consistent with previous reports using Arf1 DN in Drosophila [84]. We attributed this lethality to perturbation of post-Golgi protein transport by prolonged exposure to Arf1 DN , leading to cell death [81,85].…”

Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission

“…However, the underlying mechanisms in Drp1 regulation and mitochondrial fission remain to be elucidated. Interestingly, ARF1 is highly expressed in a variety of malignant tumors 17 , 18 and has been reported to activate the ERK pathway in breast cancer 19 . However, the biological function of ARF1 in CRC is still unknown.…”

The Role of ARF Family Proteins and Their Regulators and Effectors in Cancer Progression: A Therapeutic Perspective

“…Moreover, ARF1 regulates breast cancer cell adhesion and proliferation, being essential for EGF-mediated phosphorylation of Focal Adhesion Kinase (FAK) and Src (Schlienger et al, 2015). Furthermore, ARF1 sensitizes MDA-MB-231 breast cancer cells to the anti-tumor drugs actinomycin D and vinblastine through ERK and Akt signaling (Luchsinger et al, 2018). In prostate cancer, ARF1 promotes tumorigenesis by controlling MAPK activation and cell growth (Davis et al, 2016).…”