Deoxycytidine kinase (dCK) is a rate limiting enzyme critical for the phosphorylation of endogenous deoxynucleosides and for the anti-tumor activity of many nucleoside analogs. dCK is activated in response to ionizing radiation (IR) and it is required for the G2/M checkpoint induced by IR. However, whether dCK plays a role in radiation-induced autophagy and apoptosis is less clear. In this study, we reported that dCK decreased IR-induced total cell death and apoptosis, and increased IR-induced autophagy in SKBR3 and MDA-MB-231 breast cancer cell lines. A molecular switch exists between apoptosis and autophagy. We further demonstrated that serine 74 phosphorylation was required for the regulation of autophagy. In dCK wild-type (WT) or dCK S74E (mutant) MDA-MB-231 cell models, the expression levels of phospho-Akt, phospho-mammalian target of rapamycin (mTOR) and phospho-P70S6K significantly decreased following exposure to IR. Moreover, the ratio of Bcl-2/Beclin1 (BECN1) significantly decreased in the S74E mutant cells; however, no change was observed in the ratio of Bcl-2/BAX. Taken together, our findings indicate that phosphorylated and activated dCK inhibits IR-induced total cell death and apoptosis, and promotes IR-induced autophagy through the mTOR pathway and by inhibiting the binding of Bcl-2 protein to BECN1.
[1]Jilin Prov Canc Hosp, Canc Translat Med Lab, Changchun 130012, Jilin, Peoples R China.
[2]Jilin Univ, Sch Publ Hlth, Key Lab Radiobiol, Minist Hlth, 1163 Xinmin St, Changchun 130021, Jilin, Peoples R China.
[3]Jilin Univ, Sch Nursing, Dept Obstet & Gynecol Care, Changchun 130021, Jilin, Peoples R China.
[4]Jilin Univ, Dept Radiol, Hosp Affiliated 2, Changchun 130021, Jilin, Peoples R China.
[5]Jilin Univ, Hosp Affiliated 1, Med Records Room, Changchun 130021, Jilin, Peoples R China.
[6]Wenzhou Med Univ, Sch Publ Hlth & Management, 112 Nanliu Rd, Wenzhou 325035, Zhejiang, Peoples R China.
(8.0+极速模式)