Therapeutic strategies for head and neck cancer based on p53 status (Review)

Ota,Ichiro; Okamoto,Noritomo; Yane,Katsunari; Takahashi,Akihisa; Masui,Takashi; Hosoi,Hiroshi; Ohnishi,Takeo

doi:10.3892/etm.2012.474

Therapeutic strategies for head and neck cancer based on p53 status (Review)

Authors:
- Ichiro Ota
- Noritomo Okamoto
- Katsunari Yane
- Akihisa Takahashi
- Takashi Masui
- Hiroshi Hosoi
- Takeo Ohnishi
View Affiliations

Affiliations: Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashihara, Nara 634‑8522, Japan, Department of Otolaryngology, Nara Hospital, Kinki University School of Medicine, Ikoma, Nara 630‑0293, Japan, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371‑8511, Japan, Department of Radiation Oncology, Nara Medical University, Kashihara, Nara 634‑8522, Japan
Published online on: February 3, 2012 https://doi.org/10.3892/etm.2012.474
Pages: 585-591

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Squamous cell carcinomas of the head and neck (HNSCC) are one of the most common types of cancers worldwide, and despite advances in treatment, they still represent a clinical challenge. Inactivation of one or more components in the p53 signaling pathway is an extremely common event in human neoplasia, including HNSCC. The loss of p53 function is responsible for increased aggressiveness in cancers, while tumor chemoresistance and radioresistance can depend on deleted p53 expression, or on the expression of mutated‑p53 proteins. Thus, consideration and manipulation of the p53 status during HNSCC cancer therapy should be considered. This review discusses the p53 signaling pathways activated by various cellular stresses, including exposure to cancer therapies. The recognition of the p53 status in cancer cells is a significant factor and could provide valuable assistance during the selection of an effective therapeutic approach.

View Figures

View References

1.	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300
2.	Poeta ML, Manola J, Goldwasser MA, et al: TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 357:2552–2561. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature. 408:307–310. 2000. View Article : Google Scholar : PubMed/NCBI
4.	Guimaraes DP and Hainaut P: TP53: a key gene in human cancer. Biochimie. 84:83–93. 2002. View Article : Google Scholar : PubMed/NCBI
5.	Gasco M and Crook T: The p53 network in head and neck cancer. Oral Oncol. 39:222–231. 2003. View Article : Google Scholar : PubMed/NCBI
6.	Lowe SW: Cancer therapy and p53. Curr Opin Oncol. 7:547–553. 1995. View Article : Google Scholar
7.	Velculescu VE and El-Deiry WS: Biological and clinical importance of the p53 tumor suppressor gene. Clin Chem. 42:858–868. 1996.PubMed/NCBI
8.	Ota I, Ohnishi K, Takahashi A, et al: Transfection with mutant p53 gene inhibits heat-induced apoptosis in a head and neck cell line of human squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 47:495–501. 2000. View Article : Google Scholar : PubMed/NCBI
9.	Takahashi A: Different inducibility of radiation- or heat-induced p53-dependent apoptosis after acute or chronic irradiation in human cultured squamous cell carcinoma cells. Int J Radiat Biol. 77:215–224. 2001. View Article : Google Scholar
10.	Ohnishi K, Ota I, Takahashi A, Yane K, Matsumoto H and Ohnishi T: Transfection of mutant p53 gene depresses X-ray- or CDDP-induced apoptosis in a human squamous cell carcinoma of the head and neck. Apoptosis. 7:367–372. 2002. View Article : Google Scholar : PubMed/NCBI
11.	Asakawa I, Yoshimura H, Takahashi A, et al: Radiation-induced growth inhibition in transplanted human tongue carcinomas with different p53 gene status. Anticancer Res. 22:2037–2043. 2002.PubMed/NCBI
12.	Tamamoto T, Yoshimura H, Takahashi A, et al: Heat-induced growth inhibition and apoptosis in transplanted human head and neck squamous cell carcinomas with different status of p53. Int J Hyperthermia. 19:590–597. 2003. View Article : Google Scholar : PubMed/NCBI
13.	Yuki K, Takahashi A, Ota I, et al: Sensitization by glycerol for CDDP-therapy against human cultured cancer cells and tumors bearing mutated p53 gene. Apoptosis. 9:853–859. 2004. View Article : Google Scholar : PubMed/NCBI
14.	Lane DP and Crawford LV: T antigen is bound to a host protein in SV40-transformed cells. Nature. 278:261–263. 1979. View Article : Google Scholar : PubMed/NCBI
15.	Nigro JM, Baker SJ, Preisinger AC, et al: Mutations in the p53 gene occur in diverse human tumour types. Nature. 342:705–708. 1989. View Article : Google Scholar : PubMed/NCBI
16.	Finlay CA, Hinds PW and Levine AJ: The p53 proto-oncogene can act as a suppressor of transformation. Cell. 57:1083–1093. 1989. View Article : Google Scholar : PubMed/NCBI
17.	Hollstein M, Sidransky D, Vogelstein B and Harris CC: p53 mutations in human cancers. Science. 253:49–53. 1991. View Article : Google Scholar : PubMed/NCBI
18.	Efeyan A and Serrano M: p53: guardian of the genome and policeman of the oncogenes. Cell Cycle. 6:1006–1010. 2007. View Article : Google Scholar : PubMed/NCBI
19.	Slee EA, O'Connor DJ and Lu X: To die or not to die: how does p53 decide? Oncogene. 23:2809–2818. 2004. View Article : Google Scholar : PubMed/NCBI
20.	Vousden KH and Lu X: Live or let die: the cell's response to p53. Nat Rev Cancer. 2:594–604. 2002.
21.	Bambara RA and Jessee CB: Properties of DNA polymerases delta and epsilon, and their roles in eukaryotic DNA replication. Biochim Biophys Acta. 1088:11–24. 1991. View Article : Google Scholar : PubMed/NCBI
22.	El-Deiry WS, Tokino T, Velculescu VE, et al: WAF1, a potential mediator of p53 tumor suppression. Cell. 75:817–825. 1993. View Article : Google Scholar : PubMed/NCBI
23.	Deng C, Zhang P, Harper JW, Elledge SJ and Leder P: Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 82:675–684. 1995. View Article : Google Scholar : PubMed/NCBI
24.	Kastan MB, Zhan Q, el-Deiry WS, et al: A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 71:587–597. 1992. View Article : Google Scholar : PubMed/NCBI
25.	Smith ML, Kontny HU, Zhan Q, Sreenath A, O'Connor PM and Fornace AJ Jr: Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin. Oncogene. 13:2255–2263. 1996.PubMed/NCBI
26.	Miyashita T and Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 80:293–299. 1995. View Article : Google Scholar : PubMed/NCBI
27.	Yu J and Zhang L: No PUMA, no death: implications for p53-dependent apoptosis. Cancer Cell. 4:248–249. 2003. View Article : Google Scholar : PubMed/NCBI
28.	Owen-Schaub LB, Zhang W, Cusack JC, et al: Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol. 15:3032–3040. 1995.PubMed/NCBI
29.	Israeli D, Tessler E, Haupt Y, et al: A novel p53-inducible gene, PAG608, encodes a nuclear zinc finger protein whose overexpression promotes apoptosis. EMBO J. 16:4384–4392. 1997. View Article : Google Scholar : PubMed/NCBI
30.	Haupt S, Louria-Hayon I and Haupt Y: P53 licensed to kill? Operating the assassin. J Cell Biochem. 88:76–82. 2003. View Article : Google Scholar : PubMed/NCBI
31.	Barak Y and Oren M: Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest. EMBO J. 11:2115–2121. 1992.PubMed/NCBI
32.	Brooks CL and Gu W: Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol. 15:164–171. 2003. View Article : Google Scholar : PubMed/NCBI
33.	Valenzuela MT, Guerrero R, Nunez MI, et al: PARP-1 modifies the effectiveness of p53-mediated DNA damage response. Oncogene. 21:1108–1116. 2002. View Article : Google Scholar : PubMed/NCBI
34.	Schmidt D and Muller S: Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci USA. 99:2872–2877. 2002. View Article : Google Scholar : PubMed/NCBI
35.	Melchior F and Hengst L: SUMO-1 and p53. Cell Cycle. 1:245–249. 2002. View Article : Google Scholar
36.	Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E and Kastan MB: DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 11:3471–3481. 1997. View Article : Google Scholar : PubMed/NCBI
37.	Shieh SY, Ahn J, Tamai K, Taya Y and Prives C: The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14:289–300. 2000.PubMed/NCBI
38.	Urban G, Golden T, Aragon IV, et al: Identification of a functional link for the p53 tumor suppressor protein in dexamethasone-induced growth suppression. J Biol Chem. 278:9747–9753. 2003. View Article : Google Scholar : PubMed/NCBI
39.	Oda K, Arakawa H, Tanaka T, et al: p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 102:849–862. 2000. View Article : Google Scholar : PubMed/NCBI
40.	Saito S, Goodarzi AA, Higashimoto Y, et al: ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation. J Biol Chem. 277:12491–12494. 2002. View Article : Google Scholar : PubMed/NCBI
41.	Ohnishi T, Matsumoto H, Takahashi A, Shimura M and Majima HJ: Accumulation of mutant p53 and hsp72 by heat treatment, and their association in a human glioblastoma cell line. Int J Hyperthermia. 11:663–671. 1995. View Article : Google Scholar : PubMed/NCBI
42.	Matsumoto H, Wang X and Ohnishi T: Binding between wild-type p53 and hsp72 accumulated after UV and gamma-ray irradiation. Cancer Lett. 92:127–133. 1995. View Article : Google Scholar : PubMed/NCBI
43.	Petros AM, Gunasekera A, Xu N, Olejniczak ET and Fesik SW: Defining the p53 DNA-binding domain/Bcl-x(L)-binding interface using NMR. FEBS Lett. 559:171–174. 2004. View Article : Google Scholar : PubMed/NCBI
44.	Takahashi A, Ota I, Tamamoto T, et al: p53-dependent hyper-thermic enhancement of tumour growth inhibition by X-ray or carbon-ion beam irradiation. Int J Hyperthermia. 19:145–153. 2003. View Article : Google Scholar : PubMed/NCBI
45.	Fujiwara T, Cai DW, Georges RN, Mukhopadhyay T, Grimm EA and Roth JA: Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst. 86:1458–1462. 1994. View Article : Google Scholar : PubMed/NCBI
46.	Scardigli R, Bossi G, Blandino G, Crescenzi M, Soddu S and Sacchi A: Expression of exogenous wt-p53 does not affect normal hematopoiesis: implications for bone marrow purging. Gene Ther. 4:1371–1378. 1997. View Article : Google Scholar : PubMed/NCBI
47.	Bossi G, Mazzaro G, Porrello A, Crescenzi M, Soddu S and Sacchi A: Wild-type p53 gene transfer is not detrimental to normal cells in vivo: implications for tumor gene therapy. Oncogene. 23:418–425. 2004. View Article : Google Scholar : PubMed/NCBI
48.	Vecil GG and Lang FF: Clinical trials of adenoviruses in brain tumors: a review of Ad-p53 and oncolytic adenoviruses. J Neurooncol. 65:237–246. 2003. View Article : Google Scholar : PubMed/NCBI
49.	Pearson S, Jia H and Kandachi K: China approves first gene therapy. Nat Biotechnol. 22:3–4. 2004. View Article : Google Scholar : PubMed/NCBI
50.	Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G and Sacchi A: Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene. 25:304–309. 2006.PubMed/NCBI
51.	Bischoff JR, Kirn DH, Williams A, et al: An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 274:373–376. 1996. View Article : Google Scholar : PubMed/NCBI
52.	Bossi G and Sacchi A: Restoration of wild-type p53 function in human cancer: relevance for tumor therapy. Head Neck. 29:272–284. 2007. View Article : Google Scholar : PubMed/NCBI
53.	Ohnishi K, Ota I, Takahashi A and Ohnishi T: Glycerol restores p53-dependent radiosensitivity of human head and neck cancer cells bearing mutant p53. Br J Cancer. 83:1735–1739. 2000. View Article : Google Scholar : PubMed/NCBI
54.	Welch WJ and Brown CR: Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones. 1:109–115. 1996. View Article : Google Scholar : PubMed/NCBI
55.	Thomas PJ, Qu BH and Pedersen PL: Defective protein folding as a basis of human disease. Trends Biochem Sci. 20:456–459. 1995. View Article : Google Scholar : PubMed/NCBI
56.	Ohnishi K, Ota I, Yane K, et al: Glycerol as a chemical chaperone enhances radiation-induced apoptosis in anaplastic thyroid carcinoma cells. Mol Cancer. 1:42002. View Article : Google Scholar
57.	Imai Y, Ohnishi K, Yasumoto J, et al: Glycerol enhances radio-sensitivity in a human oral squamous cell carcinoma cell line (Ca9-22) bearing a mutant p53 gene via Bax-mediated induction of apoptosis. Oral Oncol. 41:631–636. 2005. View Article : Google Scholar : PubMed/NCBI
58.	Ohnishi T, Ohnishi K and Takahashi A: Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53. BMC Biotechnol. 2:62002. View Article : Google Scholar : PubMed/NCBI
59.	Yuki K, Takahashi A, Ota I, et al: Glycerol enhances CDDP-induced growth inhibition of thyroid anaplastic carcinoma tumor carrying mutated p53 gene. Oncol Rep. 11:821–824. 2004.PubMed/NCBI
60.	Bargonetti J, Friedman PN, Kern SE, Vogelstein B and Prives C: Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell. 65:1083–1091. 1991. View Article : Google Scholar : PubMed/NCBI
61.	Cho Y, Gorina S, Jeffrey PD and Pavletich NP: Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 265:346–355. 1994. View Article : Google Scholar : PubMed/NCBI
62.	Halazonetis TD and Kandil AN: Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to select p53 mutants. EMBO J. 12:5057–5064. 1993.PubMed/NCBI
63.	Hupp TR, Meek DW, Midgley CA and Lane DP: Regulation of the specific DNA binding function of p53. Cell. 71:875–886. 1992. View Article : Google Scholar : PubMed/NCBI
64.	Hupp TR and Lane DP: Allosteric activation of latent p53 tetramers. Curr Biol. 4:865–875. 1994. View Article : Google Scholar : PubMed/NCBI
65.	Hupp TR, Sparks A and Lane DP: Small peptides activate the latent sequence-specific DNA binding function of p53. Cell. 83:237–245. 1995. View Article : Google Scholar : PubMed/NCBI
66.	Hupp TR, Meek DW, Midgley CA and Lane DP: Activation of the cryptic DNA binding function of mutant forms of p53. Nucleic Acids Res. 21:3167–3174. 1993. View Article : Google Scholar : PubMed/NCBI
67.	Abarzua P, LoSardo JE, Gubler ML, et al: Restoration of the transcription activation function to mutant p53 in human cancer cells. Oncogene. 13:2477–2482. 1996.PubMed/NCBI
68.	Selivanova G, Iotsova V, Okan I, et al: Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med. 3:632–638. 1997. View Article : Google Scholar : PubMed/NCBI
69.	Kim AL, Raffo AJ, Brandt-Rauf PW, et al: Conformational and molecular basis for induction of apoptosis by a p53 C-terminal peptide in human cancer cells. J Biol Chem. 274:34924–34931. 1999. View Article : Google Scholar : PubMed/NCBI
70.	Ohnishi K, Inaba H, Yasumoto J, Yuki K, Takahashi A and Ohnishi T: C-terminal peptides of p53 molecules enhance radiation-induced apoptosis in human mutant p53 cancer cells. Apoptosis. 9:591–597. 2004. View Article : Google Scholar : PubMed/NCBI
71.	Selivanova G, Ryabchenko L, Jansson E, Iotsova V and Wiman KG: Reactivation of mutant p53 through interaction of a C-terminal peptide with the core domain. Mol Cell Biol. 19:3395–3402. 1999.PubMed/NCBI
72.	Foster BA, Coffey HA, Morin MJ and Rastinejad F: Pharmacological rescue of mutant p53 conformation and function. Science. 286:2507–2510. 1999. View Article : Google Scholar : PubMed/NCBI
73.	Takimoto R, Wang W, Dicker DT, Rastinejad F, Lyssikatos J and el-Deiry WS: The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein. Cancer Biol Ther. 1:47–55. 2002. View Article : Google Scholar : PubMed/NCBI
74.	Rippin TM, Bykov VJ, Freund SM, Selivanova G, Wiman KG and Fersht AR: Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene. 21:2119–2129. 2002. View Article : Google Scholar : PubMed/NCBI
75.	Bykov VJ, Issaeva N, Shilov A, et al: Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 8:282–288. 2002. View Article : Google Scholar : PubMed/NCBI
76.	Peng Y, Li C, Chen L, Sebti S and Chen J: Rescue of mutant p53 transcription function by ellipticine. Oncogene. 22:4478–4487. 2003. View Article : Google Scholar : PubMed/NCBI
77.	Vassilev LT, Vu BT, Graves B, et al: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 303:844–848. 2004. View Article : Google Scholar : PubMed/NCBI
78.	Blakely EA and Kronenberg A: Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness. Radiat Res. 150:S126–S145. 1998. View Article : Google Scholar : PubMed/NCBI
79.	Guida P, Vazquez ME and Otto S: Cytotoxic effects of low- and high-LET radiation on human neuronal progenitor cells: induction of apoptosis and TP53 gene expression. Radiat Res. 164:545–551. 2005. View Article : Google Scholar : PubMed/NCBI
80.	Demizu Y, Kagawa K, Ejima Y, et al: Cell biological basis for combination radiotherapy using heavy-ion beams and high-energy X-rays. Radiother Oncol. 71:207–211. 2004. View Article : Google Scholar : PubMed/NCBI
81.	Debus J, Jackel O, Kraft G and Wannenmacher M: Is there a role for heavy ion beam therapy? Recent Results Cancer Res. 150:170–182. 1998. View Article : Google Scholar : PubMed/NCBI
82.	Takahashi A, Matsumoto H, Yuki K, et al: High-LET radiation enhanced apoptosis but not necrosis regardless of p53 status. Int J Radiat Oncol Biol Phys. 60:591–597. 2004. View Article : Google Scholar : PubMed/NCBI
83.	Takahashi A, Matsumoto H, Furusawa Y, Ohnishi K, Ishioka N and Ohnishi T: Apoptosis induced by high-LET radiations is not affected by cellular p53 gene status. Int J Radiat Biol. 81:581–586. 2005. View Article : Google Scholar : PubMed/NCBI
84.	Takahashi A, Ohnishi K, Wang X, et al: The dependence of p53 on the radiation enhancement of thermosensitivity at different LET. Int J Radiat Oncol Biol Phys. 47:489–494. 2000. View Article : Google Scholar : PubMed/NCBI
85.	Yamakawa N, Takahashi A, Mori E, et al: High LET radiation enhances apoptosis in mutated p53 cancer cells through caspase-9 activation. Cancer Sci. 99:1455–1460. 2008. View Article : Google Scholar : PubMed/NCBI
86.	Peng Y, Zhang Q, Nagasawa H, Okayasu R, Liber HL and Bedford JS: Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation. Cancer Res. 62:6400–6404. 2002.
87.	Collis SJ, Swartz MJ, Nelson WG and DeWeese TL: Enhanced radiation and chemotherapy-mediated cell killing of human cancer cells by small inhibitory RNA silencing of DNA repair factors. Cancer Res. 63:1550–1554. 2003.PubMed/NCBI
88.	Tauchi H, Kobayashi J, Morishima K, et al: Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature. 420:93–98. 2002. View Article : Google Scholar : PubMed/NCBI
89.	Sakamoto S, Iijima K, Mochizuki D, et al: Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions. Oncogene. 26:6002–6009. 2007. View Article : Google Scholar : PubMed/NCBI
90.	Tauchi H, Matsuura S, Kobayashi J, Sakamoto S and Komatsu K: Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene. 21:8967–8980. 2002. View Article : Google Scholar : PubMed/NCBI
91.	Nelms BE, Maser RS, MacKay JF, Lagally MG and Petrini JH: In situ visualization of DNA double-strand break repair in human fibroblasts. Science. 280:590–592. 1998. View Article : Google Scholar : PubMed/NCBI
92.	Zhang Y, Lim CU, Williams ES, et al: NBS1 knockdown by small interfering RNA increases ionizing radiation mutagenesis and telomere association in human cells. Cancer Res. 65:5544–5553. 2005. View Article : Google Scholar : PubMed/NCBI
93.	Lee SJ, Dimtchev A, Lavin MF, Dritschilo A and Jung M: A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB. Oncogene. 17:1821–1826. 1998. View Article : Google Scholar : PubMed/NCBI
94.	Orlowski RZ and Baldwin AS Jr: NF-kappaB as a therapeutic target in cancer. Trends Mol Med. 8:385–389. 2002. View Article : Google Scholar : PubMed/NCBI
95.	Yamagishi N, Miyakoshi J and Takebe H: Enhanced radiosensitivity by inhibition of nuclear factor kappa B activation in human malignant glioma cells. Int J Radiat Biol. 72:157–162. 1997. View Article : Google Scholar : PubMed/NCBI
96.	Habraken Y, Jolois O and Piette J: Differential involvement of the hMRE11/hRAD50/NBS1 complex, BRCA1 and MLH1 in NF-kappaB activation by camptothecin and X-ray. Oncogene. 22:6090–6099. 2003. View Article : Google Scholar : PubMed/NCBI
97.	LaCasse EC, Baird S, Korneluk RG and MacKenzie AE: The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 17:3247–3259. 1998. View Article : Google Scholar : PubMed/NCBI
98.	Ohnishi K, Scuric Z, Schiestl RH, Okamoto N, Takahashi A and Ohnishi T: siRNA targeting NBS1 or XIAP increases radiation sensitivity of human cancer cells independent of TP53 status. Radiat Res. 166:454–462. 2006. View Article : Google Scholar : PubMed/NCBI
99.	Ohnishi K, Scuric Z, Yau D, et al: Heat-induced phosphorylation of NBS1 in human skin fibroblast cells. J Cell Biochem. 99:1642–1650. 2006. View Article : Google Scholar : PubMed/NCBI
100.	Okamoto N, Takahashi A, Ota I, et al: siRNA targeted for NBS1 enhances heat sensitivity in human anaplastic thyroid carcinoma cells. Int J Hyperthermia. 27:297–304
101.	Ohnishi K, Nagata Y, Takahashi A, Taniguchi S and Ohnishi T: Effective enhancement of X-ray-induced apoptosis in human cancer cells with mutated p53 by siRNA targeting XIAP. Oncol Rep. 20:57–61. 2008.PubMed/NCBI
102.	Nicholson KM and Anderson NG: The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 14:381–395. 2002. View Article : Google Scholar : PubMed/NCBI
103.	Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
104.	Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 4:335–348. 2004. View Article : Google Scholar : PubMed/NCBI
105.	Wang F, Arun P, Friedman J, Chen Z and Van Waes C: Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol. 9:389–395. 2009. View Article : Google Scholar : PubMed/NCBI
106.	Raimondi AR, Molinolo A and Gutkind JS: Rapamycin prevents early onset of tumorigenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model. Cancer Res. 69:4159–4166. 2009. View Article : Google Scholar : PubMed/NCBI
107.	Shaw M, Cohen P and Alessi DR: The activation of protein kinase B by H₂O₂ or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 336:241–246. 1998.
108.	Rosenzweig KE, Youmell MB, Palayoor ST and Price BD: Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clin Cancer Res. 3:1149–1156. 1997.
109.	Gupta AK, Cerniglia GJ, Mick R, et al: Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys. 56:846–853. 2003. View Article : Google Scholar : PubMed/NCBI
110.	Ohnishi K, Yasumoto J, Takahashi A and Ohnishi T: LY294002, an inhibitor of PI-3K, enhances heat sensitivity independently of p53 status in human lung cancer cells. Int J Oncol. 29:249–253. 2006.PubMed/NCBI
111.	Guertin DA and Sabatini DM: Defining the role of mTOR in cancer. Cancer Cell. 12:9–22. 2007. View Article : Google Scholar
112.	Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004. View Article : Google Scholar
113.	Beuvink I, Boulay A, Fumagalli S, et al: The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell. 120:747–759. 2005. View Article : Google Scholar : PubMed/NCBI
114.	Majumder PK, Febbo PG, Bikoff R, et al: mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 10:594–601. 2004. View Article : Google Scholar
115.	Boulay A, Zumstein-Mecker S, Stephan C, et al: Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 64:252–261. 2004. View Article : Google Scholar
116.	Mabuchi S, Altomare DA, Cheung M, et al: RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res. 13:4261–4270. 2007. View Article : Google Scholar
117.	Cao C, Subhawong T, Albert JM, et al: Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 66:10040–10047. 2006. View Article : Google Scholar : PubMed/NCBI
118.	Albert JM, Kim KW, Cao C and Lu B: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther. 5:1183–1189. 2006. View Article : Google Scholar : PubMed/NCBI
119.	Nagata Y, Takahashi A, Ohnishi K, et al: Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status. Int J Oncol. 37:1001–1010