TITLE:
Circadian Rhythms in Doxorubicin Nuclear Uptake and Clock Control of C6 Glioma Cells
AUTHORS:
Ashapurna Sarma, Vishal P. Sharma, Michael E. Geusz
KEYWORDS:
Nucleocytoplasmic Transport, Circadian Pacemaker, Glioblastoma, Exportin, Chemotherapy
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.7 No.8,
August
10,
2016
ABSTRACT: Alterations of drug
efficacy by the circadian clock are a concern when assessing drug therapies.
Circadian rhythms persist in some cancer cells and are repressed in others. A
better understanding of circadian activities generated within cancer cells
could indicate therapeutic approaches that selectively disrupt rhythms and
deprive cells of any benefits provided by circadian timing. Another option is
to induce expression of the core clock gene Per2 to suppress cancer cell
proliferation. We used the C6 rat glioblastoma cell line to identify rhythmic
cancer cell properties that could provide improved therapeutic targets. Nuclear
uptake of the anti-cancer agent doxorubicin by C6 cells showed a circadian
rhythm that was shifted six hours from the rhythm in Per2 expression. We also
observed circadian expression of the Crm1 (Xpo1) gene that is responsible for a
key component of molecular transport through nuclear pores. C6 cultures include
glioma stem cells (GSCs) that have elevated resistance to chemotherapeutic
agents. We examined C6 tumorsphere cultures formed from GSCs to determine
whether Hes1 and Bmi1 genes that maintain GSCs are under circadian clock
control. Unlike Per2 gene expression in tumorspheres, Hes1 and Bmi1 expression
did not oscillate in a circadian rhythm. These results highlight the importance
of the nuclear pore complex in cancer treatments and suggest that the nuclear
export mechanism and genes maintaining the cancer stem cell state could be
inhibited therapeutically at a particular phase of the circadian cycle while
preserving the tumor-suppressing abilities of Per2 gene expression.