αV integrin induces multicellular radioresistance in human nasopharyngeal carcinoma via activating SAPK/JNK pathway.
BACKGROUND
Tumor cells acquire the capacity of resistance to chemotherapy or radiotherapy via cell-matrix and cell-cell crosstalk. Integrins are the most important cell adhesion molecules, in which αV integrin mainly mediating the tight contact between tumor cells.


RESULTS
To investigate the role of αV integrin in multi-cellular radioresistance (MCR) of human nasopharyngeal carcinoma (NPC), we performed immunohistochemistry and Western blotting to find that the expression of αV integrin in the tumor tissue of radioresistant patients is much higher than that in radiosensitive patients. In vitro, we cultured human NPC cell line CNE-2 cells as multi-cellular spheroids (MCSs) or as monolayer cells (MCs), and found that the expression of αV integrin in MCSs is significantly higher than that in MCs. MTT, flow cytometry and clonogenic survival assays showed that MCSs are less sensitive to X-ray irradiation than MCs while blocking of αV integrin in MCSs dramatically reversed their radioresistance. Furthermore, as detected by Western blotting, MCSs displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway in presence of irradiation. Blocking of αV integrin in MCSs decreased the expression of phosphorylated JNK. Additionally, blocking of SAPK/JNK signaling pathway synergistically induced apoptosis of MCSs exposed to irradiation by increasing the expression of cleaved caspase-3. In vivo, we found that irradiation combined with αV integrin blocking treatment significantly enhanced the radiosensitivity of NPC xenografts.


CONCLUSIONS
Our results indicate a novel role of αV integrin in multi-cellular radioresistance of NPCs.
Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Juanjuan
J
Ou
Wei
W
Luan
Jia
J
Deng
Rina
R
Sa
Houjie
H
Liang
D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D039564:Integrin alphaV / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011836:Radiation Tolerance / Q000502:physiology*; D014183:Transplantation, Heterologous
D039564:Integrin alphaV; D048670:MAP Kinase Kinase 4