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2016 ; 12
(5
): 3403-3410
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Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing
autophagic cell death
#MMPMID27900012
Liu S
; Wang X
; Lu J
; Han L
; Zhang Y
; Liu Z
; Ding S
; Liu Z
; Bi D
; Niu Z
Oncol Lett
2016[Nov]; 12
(5
): 3403-3410
PMID27900012
show ga
Renal cell carcinoma (RCC) is resistant to standard radiotherapy. Ubenimex, an
aminopeptidase N inhibitor, is widely used as an adjunct therapy after surgery to
enhance the function of immunocompetent cells and confer antitumor effects. Our
previous study demonstrated that ubenimex induces autophagic cell death in RCC
cells. Recently, the molecular mechanism of autophagy induction has been
associated with radiosensitivity in RCC cells. In the present study, the ability
of ubenimex to enhance RCC cell sensitivity to radiation via the induction of
autophagic cell death was determined, and the mechanism of action of this effect
was investigated. The 786-O and OS-RC-2 human RCC cell lines were treated with
0.5 mg/ml ubenimex and different doses of irradiation (IR). The cell viability
was measured using a colony-formation assay and flow cytometry. Acridine orange
(AO)-ethidium bromide (EB) staining was assessed by fluorescence microscopy as an
indicator of autophagic cell death. Protein expression was assessed by western
blotting. Autophagosomes were evaluated using transmission electron microscopy.
RCC cells were used to evaluate the sensitivity to radiation using clonogenic
survival and lactate dehydrogenase assays. Furthermore, these parameters were
also tested at physiological oxygen levels. The AO-EB staining and flow cytometry
of the OS-RC-2 cells indicated that the combined treatment significantly enhanced
autophagic cell death compared with ubenimex or IR alone. Therefore, treatment
with ubenimex did not significantly alter cell cycle progression but increased
cell death when combined with radiation. An Akt agonist could significantly
weaken this effect, indicating that ubenimex may act as an Akt inhibitor.
Furthermore, the western blot analysis indicated that the combined treatment
inhibited the Akt signaling pathway compared with ubenimex treatment or IR alone.
Ubenimex may enhance RCC cell sensitivity to radiation by inducing cell
autophagy. This induction changes the role of autophagy from protective to lethal
in vitro, and this switch is associated with the inhibition of the Akt signaling
pathway.
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