Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells.
Activation of Akt, or protein kinase B, is frequently observed in human cancers. It has been demonstrated that PI3K activation leads to radiation resistance. Here, the role of PI3K/Akt/COX-2 pathway in the resistance to radiation in human cervical cancer HeLa cells is explored. Cultured HeLa cells were randomly assigned to five treatment groups: control, radiation, LY294002, PI3K antagonist, and the COX-2-antagonist celecoxib, with the objective of determining the role of PI3K/Akt/COX-2 pathway in the radiation resistance of HeLa cells. The cell survival ratios were computed by clone formation. To calculate the quasi-threshold dose (Dq), mean lethal dose (D(0)), survival fraction at 2 Gy radiation dose (SF(2)), and radiosensitization ratio, the cell survival curves were fitted to the one-hit multitarget model. The protein expression profiles for pAkt, Akt, COX-2, Bad, and pBad were detected by Western blot analysis, and the mRNA expression profiles for COX-2 and Bad were analyzed by RT-polymerase chain reaction. Treatment with a combination of celecoxib, LY294002, and radiation resulted in elevated Dq, D(0), and SF(2), and increased radiosensitivity in HeLa cells. The PI3K/Akt/COX-2 pathway was activated by radiation, whereas celecoxib inhibited the activation of the PI3K/Akt/COX-2 axis through several targets. Our results indicate that the activated PI3K/Akt/COX-2 signal transduction pathway was the main cause for decline in radiosensitivity in HeLa cells. This study proposes that the inhibition of the PI3K/Akt/COX-2 pathway can synergistically enhance radiation efficacy.
Xia
Shu
S
Department of Oncology, The Tong Ji Hospital, TongJi Medical College, HuaZhong University of Science and Technology, Wu Han, China. xiashu1900@yahoo.com.cn
Zhao
Yin
Y
Yu
Shiying
S
Zhang
Mengxian
M
D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013449:Sulfonamides / Q000494:pharmacology; D014965:X-Rays; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D000068579:Celecoxib; D002867:Chromones; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C496540:PTGS2 protein, human