@Article{096504017X15049221237147,
AUTHOR = {Huimin Zhang, Yuhui Pang, Chuanbao Ma, Jianying Li, Huaquan Wang, Zonghong Shao},
TITLE = {ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib  via Promoting Prosurvival Autophagy},
JOURNAL = {Oncology Research},
VOLUME = {26},
YEAR = {2018},
NUMBER = {3},
PAGES = {421--429},
URL = {http://www.techscience.com/or/v26n3/56654},
ISSN = {1555-3906},
ABSTRACT = {Resistance to bortezomib (BZ) is the major problem that largely limits its clinical application in multiple 
myeloma treatment. In the current study, we investigated whether ClC5, a member of the chloride channel 
family, is involved in this process. The MTT assay showed that BZ treatment decreased cell viability in three 
multiple myeloma cell lines (ARH77, U266, and SKO-007), with IC50 values of 2.83, 4.37, and 1.91 nM, 
respectively. Moreover, BZ increased the conversion of LC3B-I to LC3B-II and expressions of beclin-1 
and ATG5, concomitantly with a decreased p62 expression. Pharmacological inhibition of autophagy with 
3-MA facilitated cell death in response to BZ treatment. Additionally, BZ increased ClC5 protein expression 
in ARH77, U266, and SKO-007 cells. Knockdown of ClC5 with small interfering RNA sensitized cells to 
BZ treatment, and upregulation of ClC5 induced chemoresistance to BZ. Furthermore, ClC5 downregulation 
promoted BZ-induced LC3B-I to LC3B-II conversion and beclin-1 expression, whereas overexpression of 
ClC5 showed the opposite results in ARH77 cells. Finally, BZ induced dephosphorylation of AKT and mTOR, 
which was significantly attenuated by ClC5 inhibition. However, ClC5 upregulation further enhanced AKT 
and mTOR dephosphorylation induced by BZ. Our study demonstrates that ClC5 induces chemoresistance of 
multiple myeloma cells to BZ via increasing prosurvival autophagy by inhibiting the AKT–mTOR pathway. 
These data suggest that ClC5 may play a critical role in future multiple myeloma treatment strategies.},
DOI = {10.3727/096504017X15049221237147}
}