title: Radiation/paclitaxel treatment of p53-abnormal non-small cell lung cancer xenograft tumor and associated mechanism.
abstract: BACKGROUND
  Mutations in key tumor suppressor genes such as tumor protein 53 (TP53) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) are the main genetic alterations in cancers. TP53 mutations have been found in most patients with non-small cell lung cancer (NSCLC), whereas PTEN mutations are rarely found in lung cancer, though most NSCLCs lack PTEN protein synthesis. However, the signaling involved in radio- and chemotherapy of NSCLC with wild-type PTEN and nonfunctional p53 is not clearly understood.
  
  
  METHODS
  In this study, we established a xenograft tumor model with H358 NSCLC cells expressing wild-type PTEN, but nonfunctional p53. Protein expression and phosphorylation of PTEN and its downstream signal molecules in NSCLC tissues were detected by Western blot.
  
  
  RESULTS
  We demonstrated that radiation and paclitaxel alone inhibited tumor growth, but a combined therapy of radiation and paclitaxel was more effective in inhibiting NSCLC tumor growth. Interestingly, both radiation and paclitaxel significantly increased PTEN protein expression and phosphorylation. Further identification of the affected PTEN downstream molecules showed that Akt phosphorylation at Ser(473) and Thr(308) residues was significantly decreased, whereas Bax and cleaved caspase-3 levels were significantly increased in tumor tissues treated with both radiation and paclitaxel. The combined treatment was more effective than either treatment alone in regulating the studied molecules. We also found that paclitaxel, but not radiation, inhibited phosphoinositide 3-kinase (PI3K) activity.
  
  
  CONCLUSIONS
  Our study suggested that a PTEN-PI3K-Akt-Bax signaling cascade is involved in the therapeutic effect of combined radiation/paclitaxel treatment in NSCLC without p53 expression. Our study also suggested that PTEN is an ideal target in tumors with wild-type PTEN and a lack of functional p53.
authors.affiliation: Department of Radiology, Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhao
authors.forename: Xianjing
authors.initials: X
authors.lastname: Peng
authors.forename: Jian
authors.initials: J
authors.lastname: Liang
authors.forename: Xin
authors.initials: X
authors.lastname: Deng
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D059248:Chemoradiotherapy; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009368:Neoplasm Transplantation; D051058:Oncogene Protein v-akt / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D058539:Phosphatidylinositol 3-Kinase / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D058539:Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D053148:Caspase 3; D017239:Paclitaxel