Etoposide Triggers Cellular Senescence by Inducing Multiple Centrosomes and Primary Cilia in Adrenocortical Tumor Cells

Abstract

Etoposide (ETO) has been used in treating adrenocortical tumor (ACT) cells. Our previous study showed that ETO inhibits ACT cell growth. In the present study, we show that ETO treatment at IC50 (10 μM) inhibited ACT cell growth by inducing cellular senescence rather than apoptosis. Several markers of cellular senescence, including enlarged nuclei, activated senescence-associated β-galactosidase activity, elevated levels of p53 and p21, and down-regulation of Lamin B1, were observed. We further found that ETO induced multiple centrosomes. The inhibition of multiple centrosomes accomplished by treating cells with either roscovitine or centrinone or through the overexpression of NR5A1/SF-1 alleviated ETO-induced senescence, suggesting that ETO triggered senescence via multiple centrosomes. Primary cilia also played a role in ETO-induced senescence. In the mechanism, DNA-PK-Chk2 signaling was activated by ETO treatment; inhibition of this signaling cascade alleviated multiple ETO-induced centrosomes and primary cilia followed by reducing cellular senescence. In addition to DNA damage signaling, autophagy was also triggered by ETO treatment for centrosomal events and senescence. Importantly, the inactivation of DNA-PK-Chk2 signaling reduced ETO-triggered autophagy; however, the inhibition of autophagy did not affect DNA-PK-Chk2 activation. Thus, ETO activated the DNA-PK-Chk2 cascade to facilitate autophagy. The activated autophagy further induced multiple centrosomes and primary cilia followed by triggering senescence.

Environmental Barriers and Functional Outcomes in Patients with Schizophrenia in Taiwan: The Capacity-Performance Discrepancy

“…We also found that the capacity-performance discrepancy was significantly higher in patients with moderate schizophrenia with categories e110, e115, and e120 accessibility barriers than in patients with moderate schizophrenia without categories e110, e115, and e120 accessibility barriers. Multiple environmental barriers may also induce psychological and oxidative stress [ 35 ] and be associated with functional decline and senescence [ 36 ]. While this finding is similar to those of previous studies assessing other chronic disabling conditions [ 17 ], we found that the capacity-performance discrepancy was significantly lower in patients with severe schizophrenia with category e120 accessibility barriers than in patients with severe schizophrenia without the category e120 accessibility barrier.…”

Modulation of Autophagy in Adrenal Tumors

“…RGZ treatment also induced upregulation of Beclin-1 and LAMP-1, two proteins involved in different steps of the autophagic process (42). Another more recent report related induction of autophagy with cell death in ACC (43). In fact, it was shown that etoposide treatment inhibited the growth of the Y1 cells (murine adrenocortical tumor cell line) by inducing cellular senescence rather than apoptosis.…”

“…Interestingly, the authors hypothesize that, upon etoposide treatment, Y1 cells start to grow cilia for cell cycle arrest and possibly, to gain the ability to become drug-resistant cells. This hypothesis should be further investigated in the future in order to improve therapeutic efficacy (43).…”

Magnetic bioassembly platforms for establishing craniofacial exocrine gland organoids as aging in vitro models

“…To induce the cellular senescence in LG organoids, etoposide treatment (5-25 μM) was performed according to previous reports [34,37,38]. Next, cellular senescence in the organoids can be determined by measuring β-galactosidase activity, a known marker for senescent cells (Fig 6).…”