順鉑經常與紫杉醇聯合進行合併性的化學療法，以治療膀胱尿路上皮癌。然而，如同其它類癌症治療方法所面臨的問題，交叉抗藥性使得順鉑的發展受到挑戰，阻礙其成功治療膀胱尿路上皮癌的經驗。因此，當務之急是了解順鉑所誘發的對癌症治療藥物抗藥性的根本機制，以便發展出新對策。本研究利用報導基因法和in vivo DNA 結合實驗，評估ABCB1 基因和ABCC2 基因的活化是否直接受到CEBPD 的調控。本研究
也利用抑制蛋白表現和抗癌藥物的效果實驗，以釐清存在於膀胱尿路上皮癌細胞內的上皮細胞生長因子接受體 (EGFR) 以及訊息傳遞及轉錄因子3 (STAT3) 此二者與通過順鉑誘導CEBPD 的表現是否有關聯。最後，本研究進行動物異種移植實驗，以測試Gefitinib 和S31-201（Stat3 抑制劑）兩者在逆轉順鉑敏感性，達到殺死膀胱尿路上皮癌細胞的效果。CEBPD 持續性地表現在已接受化學療法治療的病患身上；CEBPD也在具有順鉑抗藥性的膀胱尿路上皮癌細胞產生反應。當接受順鉑治療時，所誘導的CEBPD 表現活化了ABCB1 基因和ABCC2 基因。上皮細胞生長因子接受體/訊息傳遞及轉入因子3 的活化有助於順鉑於膀胱尿路上皮癌細胞內，誘導CEBPD 表現。艾瑞莎和S31-201 明顯減少了CEBPD 表現，但增強了順鉑的敏感性、促進具有順鉑抗藥性的NTUB1/P 細胞對紫杉醇敏感性和NTUB1/P 異種移植腫瘤的敏感性。本研究結果呈現在具有順鉑抗藥性的膀胱尿路上皮癌細胞內，活化CEBPD 所伴隨的風險；同時，也提出藉由合併順鉑和艾瑞莎或S31-201 的策略，治療膀胱尿路上皮癌或具有順鉑抗藥性的膀胱尿路上皮癌。

Urothelial carcinoma of urinary bladder (UCUB) is the fourth most common malignancy in men, and the tenth most common in women. Anticancer drug cisplatin (CDDP) is highly used in the therapy of UCUB. In addition, CDDP is frequently combination chemotherapy with paclitaxel (PTX) used in UCUB therapies. However, as well as other types of cancers, the development of CDDP cross-resistance remains a challenge problem hindering the
successful treatment of UCUB. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug cross-resistance to develop novel strategies is urgent. CCAAT/enhancer binding protein delta (CEBPD) is expressed at a relatively low level under normal physiological conditions and can be up-regulated by a variety of extracellular
stimuli including IL-1β, PGE2, TNFα and stress like as starvation of serum and anticancer drugs. Actually, the function of CEBPD is more than serves as a tumor suppressor; several reports suggested that CEBPD also play an oncogenic role in certain conditions. For instance, recent study have demonstrated that CDDP could induce CEBPD-mediated
anti-apoptosis pathway in UCUB cells. However, how CDDP induces cross-resistance with PTX through transcription regulation of genes involved in anti-apoptosis remains largely unexplored. In this study, we found that the ABCB1 and ABCC2 genes were activated by CEBPD upon CDDP treatment. The EGFR/STAT3 pathway contributed to the CDDP-induced CEBPD expression in the UCUB cells. Both Gefitinib and S3I-201 significantly decreased CEBPD expression and enhanced the sensitivity of CDDP or PTX
of CDDP-resistant NTUB1/P cells or NTUB1/P xenograft tumors. Taken together, our results demonstrate the risk of CEBPD activation in CDDP-resistant UCUB cells and suggest a potentially therapeutic strategy for treating patients with UCUB or UCUB with CDDP-induced PTX resistance via a combination of CDDP and Gefitinib or S3I-201.

1. Turchi, J.J., Nitric oxide and cisplatin resistance: NO easy answers. Proc Natl Acad
Sci U S A, 2006. 103(12): p. 4337‐8.
2. Gosland, M., et al., Insights into mechanisms of cisplatin resistance and potential
for its clinical reversal. Pharmacotherapy, 1996. 16(1): p. 16‐39.
3. Wang, D. and S.J. Lippard, Cellular processing of platinum anticancer drugs. Nat
Rev Drug Discov, 2005. 4(4): p. 307‐20.
4. Torigoe, T., et al., Cisplatin resistance and transcription factors. Curr Med Chem
Anticancer Agents, 2005. 5(1): p. 15‐27.
5. Tatokoro, M., et al., Potential role of Hsp90 inhibitors in overcoming cisplatin
resistance of bladder cancer‐initiating cells. Int J Cancer, 2012. 131(4): p. 987‐96.
6. Shinohara, N., et al., Evaluation of multiple drug resistance in human bladder
cancer cell lines. J Urol, 1993. 150(2 Pt 1): p. 505‐9.
7. Casares, C., et al., Reactive oxygen species in apoptosis induced by cisplatin: review
of physiopathological mechanisms in animal models. Eur Arch Otorhinolaryngol,
2012. 269(12): p. 2455‐9.
8. Uslu, R. and B. Bonavida, Involvement of the mitochondrion respiratory chain in the
synergy achieved by treatment of human ovarian carcinoma cell lines with both
tumor necrosis factor‐alpha and cis‐diamminedichloroplatinum. Cancer, 1996.
77(4): p. 725‐32.
9. Miyajima, A., et al., Role of reactive oxygen species in
cis‐dichlorodiammineplatinum‐induced cytotoxicity on bladder cancer cells. Br J
Cancer, 1997. 76(2): p. 206‐10.
10. Benhar, M., et al., Enhanced ROS production in oncogenically transformed cells
potentiates c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase
activation and sensitization to genotoxic stress. Mol Cell Biol, 2001. 21(20): p.
6913‐26.
11. Valko, M., et al., Free radicals and antioxidants in normal physiological functions
and human disease. Int J Biochem Cell Biol, 2007. 39(1): p. 44‐84.
12. Roth, B.J., et al., Significant activity of paclitaxel in advanced transitional‐cell
carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology
Group. J Clin Oncol, 1994. 12(11): p. 2264‐70.
13. Meluch, A.A., et al., Paclitaxel and gemcitabine chemotherapy for advanced
transitional‐cell carcinoma of the urothelial tract: a phase II trial of the Minnie
pearl cancer research network. J Clin Oncol, 2001. 19(12): p. 3018‐24.
14. Bellmunt, J., et al., Gemcitabine/paclitaxel‐based three‐drug regimens in advanced
urothelial cancer. Eur J Cancer, 2000. 36 Suppl 2: p. 17‐25.
15. Rowinsky, E.K. and R.C. Donehower, Paclitaxel (taxol). N Engl J Med, 1995. 332(15):
p. 1004‐14.
16. Haldar, S., J. Chintapalli, and C.M. Croce, Taxol induces bcl‐2 phosphorylation and
death of prostate cancer cells. Cancer Res, 1996. 56(6): p. 1253‐5.
17. Ranganathan, S., et al., Altered beta‐tubulin isotype expression in
paclitaxel‐resistant human prostate carcinoma cells. Br J Cancer, 1998. 77(4): p.
562‐6.
18. Dumontet, C., et al., Resistance mechanisms in human sarcoma mutants derived by
single‐step exposure to paclitaxel (Taxol). Cancer Res, 1996. 56(5): p. 1091‐7.
19. Wang, T.H., et al., Microtubule‐interfering agents activate c‐Jun N‐terminal
kinase/stress‐activated protein kinase through both Ras and apoptosis
signal‐regulating kinase pathways. J Biol Chem, 1998. 273(9): p. 4928‐36.
20. Amato, S.F., et al., Transient stimulation of the c‐Jun‐NH2‐terminal kinase/activator
protein 1 pathway and inhibition of extracellular signal‐regulated kinase are early
effects in paclitaxel‐mediated apoptosis in human B lymphoblasts. Cancer Res,
1998. 58(2): p. 241‐7.
21. Lee, L.F., et al., Identification of tumor‐specific paclitaxel (Taxol)‐responsive
regulatory elements in the interleukin‐8 promoter. Mol Cell Biol, 1997. 17(9): p.
5097‐105.
22. Das, K.C. and C.W. White, Activation of NF‐kappaB by antineoplastic agents. Role of
protein kinase C. J Biol Chem, 1997. 272(23): p. 14914‐20.
23. Perera, P.Y., N. Qureshi, and S.N. Vogel, Paclitaxel (Taxol)‐induced NF‐kappaB
translocation in murine macrophages. Infect Immun, 1996. 64(3): p. 878‐84.
24. Tishler, R.B., et al., Microtubule‐active drugs taxol, vinblastine, and nocodazole
increase the levels of transcriptionally active p53. Cancer Res, 1995. 55(24): p.
6021‐5.
25. Gately, D.P., et al., Cisplatin and taxol activate different signal pathways regulating
cellular injury‐induced expression of GADD153. Br J Cancer, 1996. 73(1): p. 18‐23.
26. Lee, L.F., et al., Taxol‐dependent transcriptional activation of IL‐8 expression in a
subset of human ovarian cancer. Cancer Res, 1996. 56(6): p. 1303‐8.
27. Watson, J.M., et al., Identification of the structural region of taxol that may be
responsible for cytokine gene induction and cytotoxicity in human ovarian cancer
cells. Cancer Chemother Pharmacol, 1998. 41(5): p. 391‐7.
28. Moos, P.J. and F.A. Fitzpatrick, Taxane‐mediated gene induction is independent of
microtubule stabilization: induction of transcription regulators and enzymes that modulate inflammation and apoptosis. Proc Natl Acad Sci U S A, 1998. 95(7): p.
3896‐901.
29. Ullrich, A., et al., Human epidermal growth factor receptor cDNA sequence and
aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.
Nature, 1984. 309(5967): p. 418‐25.
30. Wells, A., EGF receptor. Int J Biochem Cell Biol, 1999. 31(6): p. 637‐43.
31. Colquhoun, A.J. and J.K. Mellon, Epidermal growth factor receptor and bladder
cancer. Postgrad Med J, 2002. 78(924): p. 584‐9.
32. Neal, D.E., et al., The epidermal growth factor receptor and the prognosis of
bladder cancer. Cancer, 1990. 65(7): p. 1619‐25.
33. Sauter, G., et al., Epidermal‐growth‐factor‐receptor expression is associated with
rapid tumor proliferation in bladder cancer. Int J Cancer, 1994. 57(4): p. 508‐14.
34. Ciardiello, F., et al., Antitumor effect and potentiation of cytotoxic drugs activity in
human cancer cells by ZD‐1839 (Iressa), an epidermal growth factor
receptor‐selective tyrosine kinase inhibitor. Clin Cancer Res, 2000. 6(5): p. 2053‐63.
35. Shrader, M., et al., Gefitinib reverses TRAIL resistance in human bladder cancer cell
lines via inhibition of AKT‐mediated X‐linked inhibitor of apoptosis protein
expression. Cancer Res, 2007. 67(4): p. 1430‐5.
36. Persons, D.L., et al., Cisplatin‐induced activation of mitogen‐activated protein
kinases in ovarian carcinoma cells: inhibition of extracellular signal‐regulated
kinase activity increases sensitivity to cisplatin. Clin Cancer Res, 1999. 5(5): p.
1007‐14.
37. Wang, X., J.L. Martindale, and N.J. Holbrook, Requirement for ERK activation in
cisplatin‐induced apoptosis. J Biol Chem, 2000. 275(50): p. 39435‐43.
38. Balamurugan, K. and E. Sterneck, The many faces of C/EBPdelta and their
relevance for inflammation and cancer. Int J Biol Sci, 2013. 9(9): p. 917‐33.
39. Ko, C.Y., et al., CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3
expression inhibits macrophage‐mediated phagocytosis of dying neuron cells.
Neurobiol Aging. 33(2): p. 422 e11‐25.
40. Wang, J.M., et al., Functional role of NF‐IL6beta and its sumoylation and
acetylation modifications in promoter activation of cyclooxygenase 2 gene. Nucleic
Acids Res, 2006. 34(1): p. 217‐31.
41. Lai, P.H., et al., HDAC1/HDAC3 modulates PPARG2 transcription through the
sumoylated CEBPD in hepatic lipogenesis. Biochim Biophys Acta, 2008. 1783(10): p.
1803‐14.
42. Ko, C.Y., et al., Epigenetic silencing of CCAAT/enhancer‐binding protein delta activity
by YY1/polycomb group/DNA methyltransferase complex. J Biol Chem, 2008. 283(45): p. 30919‐32.
43. Pan, Y.C., et al., CEBPD reverses RB/E2F1‐mediated gene repression and
participates in HMDB‐induced apoptosis of cancer cells. Clin Cancer Res. 16(23): p.
5770‐80.
44. Tang, D., G.S. Sivko, and J.W. DeWille, Promoter methylation reduces C/EBPdelta
(CEBPD) gene expression in the SUM‐52PE human breast cancer cell line and in
primary breast tumors. Breast Cancer Res Treat, 2006. 95(2): p. 161‐70.
45. Ikezoe, T., et al., CCAAT/enhancer‐binding protein delta: a molecular target of
1,25‐dihydroxyvitamin D3 in androgen‐responsive prostate cancer LNCaP cells.
Cancer Res, 2005. 65(11): p. 4762‐8.
46. Gery, S., et al., C/EBPdelta expression in a BCR‐ABL‐positive cell line induces growth
arrest and myeloid differentiation. Oncogene, 2005. 24(9): p. 1589‐97.
47. Wu, S.R., et al., CCAAT/enhancer‐binding protein delta mediates tumor necrosis
factor alpha‐induced Aurora kinase C transcription and promotes genomic
instability. J Biol Chem. 286(33): p. 28662‐70.
48. Balamurugan, K., et al., The tumour suppressor C/EBPdelta inhibits FBXW7
expression and promotes mammary tumour metastasis. EMBO J. 29(24): p.
4106‐17.
49. Sanford, D.C. and J.W. DeWille, C/EBPdelta is a downstream mediator of IL‐6
induced growth inhibition of prostate cancer cells. Prostate, 2005. 63(2): p. 143‐54.
50. Koh, M.Y., T.R. Spivak‐Kroizman, and G. Powis, Inhibiting the hypoxia response for
cancer therapy: the new kid on the block. Clin Cancer Res, 2009. 15(19): p. 5945‐6.
51. Yun, Z., et al., Inhibition of PPAR gamma 2 gene expression by the HIF‐1‐regulated
gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia. Dev
Cell, 2002. 2(3): p. 331‐41.
52. Tang, Y., et al., Effect of hypoxic preconditioning on brain genomic response before
and following ischemia in the adult mouse: identification of potential
neuroprotective candidates for stroke. Neurobiol Dis, 2006. 21(1): p. 18‐28.
53. Huang, A.M., et al., The Cebpd (C/EBPdelta) gene is induced by luteinizing
hormones in ovarian theca and interstitial cells but is not essential for mouse ovary
function. PLoS One, 2007. 2(12): p. e1334.
54. Lekstrom‐Himes, J. and K.G. Xanthopoulos, Biological role of the
CCAAT/enhancer‐binding protein family of transcription factors. J Biol Chem, 1998.
273(44): p. 28545‐8.
55. Huang, A.M., et al., Loss of CCAAT/enhancer binding protein delta promotes
chromosomal instability. Oncogene, 2004. 23(8): p. 1549‐57.
56. Thangaraju, M., et al., C/EBPdelta is a crucial regulator of pro‐apoptotic gene expression during mammary gland involution. Development, 2005. 132(21): p.
4675‐85.
57. Wang, J.M., J.T. Tseng, and W.C. Chang, Induction of human NF‐IL6beta by
epidermal growth factor is mediated through the p38 signaling pathway and cAMP
response element‐binding protein activation in A431 cells. Mol Biol Cell, 2005.
16(7): p. 3365‐76.
58. Hour, T.C., et al., Transcriptional up‐regulation of SOD1 by CEBPD: a potential
target for cisplatin resistant human urothelial carcinoma cells. Biochem Pharmacol.
80(3): p. 325‐34.
59. Cho, S., et al., Notch1 regulates the expression of the multidrug resistance gene
ABCC1/MRP1 in cultured cancer cells. Proc Natl Acad Sci U S A, 2011. 108(51): p.
20778‐83.
60. Hou, H., et al., Tunicamycin Potentiates Cisplatin Anticancer Efficacy through the
DPAGT1/Akt/ABCG2 Pathway in Mouse Xenograft Models of Human Hepatocellular
Carcinoma. Mol Cancer Ther, 2013. 12(12): p. 2874‐84.
61. Taniguchi, K., et al., A human canalicular multispecific organic anion transporter
(cMOAT) gene is overexpressed in cisplatin‐resistant human cancer cell lines with
decreased drug accumulation. Cancer Res, 1996. 56(18): p. 4124‐9.
62. Esteva, F.J., et al., Chemotherapy of metastatic breast cancer: what to expect in
2001 and beyond. Oncologist, 2001. 6(2): p. 133‐46.
63. Ambudkar, S.V., et al., Biochemical, cellular, and pharmacological aspects of the
multidrug transporter. Annu Rev Pharmacol Toxicol, 1999. 39: p. 361‐98.
64. Raggers, R.J., I. Vogels, and G. van Meer, Multidrug‐resistance P‐glycoprotein
(MDR1) secretes platelet‐activating factor. Biochem J, 2001. 357(Pt 3): p. 859‐65.
65. Raaijmakers, M.H., et al., ABCB1 modulation does not circumvent drug extrusion
from primitive leukemic progenitor cells and may preferentially target residual
normal cells in acute myelogenous leukemia. Clin Cancer Res, 2006. 12(11 Pt 1): p.
3452‐8.
66. Fletcher, J.I., et al., ABC transporters in cancer: more than just drug efflux pumps.
Nat Rev Cancer, 2010. 10(2): p. 147‐56.
67. Hour, T.C., et al., Transcriptional up‐regulation of SOD1 by CEBPD: a potential
target for cisplatin resistant human urothelial carcinoma cells. Biochem Pharmacol,
2010. 80(3): p. 325‐34.
68. Hasegawa, S., et al., Expression of multidrug resistance‐associated protein (MRP),
MDR1 and DNA topoisomerase II in human multidrug‐resistant bladder cancer cell
lines. Br J Cancer, 1995. 71(5): p. 907‐13.
69. Kimiya, K., et al., Establishment and characterization of doxorubicin‐resistant human bladder cancer cell line, KK47/ADM. J Urol, 1992. 148(2 Pt 1): p. 441‐5.
70. Nakagawa, M., et al., Clinical significance of multi‐drug resistance associated
protein and P‐glycoprotein in patients with bladder cancer. J Urol, 1997. 157(4): p.
1260‐4; discussion 1264‐5.
71. Judson, P.L., et al., Cisplatin inhibits paclitaxel‐induced apoptosis in
cisplatin‐resistant ovarian cancer cell lines: possible explanation for failure of
combination therapy. Cancer Res, 1999. 59(10): p. 2425‐32.
72. Yeh, M.Y., et al., Establishment and characterization of a human urinary bladder
carcinoma cell line (TSGH‐8301). J Surg Oncol, 1988. 37(3): p. 177‐84.
73. Yu, H.J., et al., Characterization of a newly established human bladder carcinoma
cell line, NTUB1. J Formos Med Assoc, 1992. 91(6): p. 608‐13.
74. Kim, W.T., et al., S100A9 and EGFR gene signatures predict disease progression in
muscle invasive bladder cancer patients after chemotherapy. Ann Oncol, 2014.
25(5): p. 974‐9.
75. Silva, C.M., Role of STATs as downstream signal transducers in Src family
kinase‐mediated tumorigenesis. Oncogene, 2004. 23(48): p. 8017‐23.
76. Sriuranpong, V., et al., Epidermal growth factor receptor‐independent constitutive
activation of STAT3 in head and neck squamous cell carcinoma is mediated by the
autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer
Res, 2003. 63(11): p. 2948‐56.
77. Flaig, T.W., et al., Dual epidermal growth factor receptor and vascular endothelial
growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to
cisplatin in a dose‐ and sequence‐dependent manner. BJU Int, 2009. 103(12): p.
1729‐37.
78. Sen, M., et al., Targeting Stat3 abrogates EGFR inhibitor resistance in cancer. Clin
Cancer Res. 18(18): p. 4986‐96.
79. Lin, L., et al., A novel small molecule inhibits STAT3 phosphorylation and DNA
binding activity and exhibits potent growth suppressive activity in human cancer
cells. Mol Cancer, 2010. 9: p. 217.
80. Clifford, S.C., et al., Increased mdr1 gene transcript levels in high‐grade carcinoma
of the bladder determined by quantitative PCR‐based assay. Br J Cancer, 1994.
69(4): p. 680‐6.
81. Tada, Y., et al., MDR1 gene overexpression and altered degree of methylation at
the promoter region in bladder cancer during chemotherapeutic treatment. Clin
Cancer Res, 2000. 6(12): p. 4618‐27.
82. Floyd, J.W., C.W. Lin, and G.R. Prout, Jr., Multi‐drug resistance of a
doxorubicin‐resistant bladder cancer cell line. J Urol, 1990. 144(1): p. 169‐71.
83. Tada, Y., et al., Increased expression of multidrug resistance‐associated proteins in
bladder cancer during clinical course and drug resistance to doxorubicin. Int J
Cancer, 2002. 98(4): p. 630‐5.
84. Hoffmann, A.C., et al., MDR1 and ERCC1 expression predict outcome of patients
with locally advanced bladder cancer receiving adjuvant chemotherapy. Neoplasia,
2010. 12(8): p. 628‐36.
85. Piulats, J.M., et al., Molecular mechanisms behind the resistance of cisplatin in
germ cell tumours. Clin Transl Oncol, 2009. 11(12): p. 780‐6.
86. Yagoda, A., Chemotherapy of Urothelial Tract Tumors. Cancer, 1987. 60(3): p.
574‐585.
87. Yeh, W.C., et al., Cascade regulation of terminal adipocyte differentiation by three
members of the C/EBP family of leucine zipper proteins. Genes Dev, 1995. 9(2): p.
168‐81.
88. Weiland, T., et al., Sensitization by 5‐azacytidine toward death receptor‐induced
hepatic apoptosis. J Pharmacol Exp Ther, 2009. 328(1): p. 107‐15.
89. Chuang, C.H., et al., The combination of the prodrugs perforin‐CEBPD and
perforin‐granzyme B efficiently enhances the activation of caspase signaling and
kills prostate cancer. Cell Death Dis, 2014. 5: p. e1220.
90. Wang, S.M., et al., Increase of zinc finger protein 179 in response to
CCAAT/enhancer binding protein delta conferring an antiapoptotic effect in
astrocytes of Alzheimer's disease. Mol Neurobiol, 2015. 51(1): p. 370‐82.
91. Weinstein, R.S., et al., Relationship of the expression of the multidrug resistance
gene product (P‐glycoprotein) in human colon carcinoma to local tumor
aggressiveness and lymph node metastasis. Cancer Res, 1991. 51(10): p. 2720‐6.
92. Fojo, A.T., et al., Intrinsic drug resistance in human kidney cancer is associated with
expression of a human multidrug‐resistance gene. J Clin Oncol, 1987. 5(12): p.
1922‐7.
93. Campa, D., et al., A comprehensive study of polymorphisms in ABCB1, ABCC2 and
ABCG2 and lung cancer chemotherapy response and prognosis. Int J Cancer.
131(12): p. 2920‐8.
94. Takiguchi, M., The C/EBP family of transcription factors in the liver and other
organs. Int J Exp Pathol, 1998. 79(6): p. 369‐91.
95. Conze, D., et al., Autocrine production of interleukin 6 causes multidrug resistance
in breast cancer cells. Cancer Res, 2001. 61(24): p. 8851‐8.
96. Zhou, B.B. and S.J. Elledge, The DNA damage response: putting checkpoints in
perspective. Nature, 2000. 408(6811): p. 433‐9.
97. Pearce, A.K. and T.C. Humphrey, Integrating stress‐response and cell‐cycle checkpoint pathways. Trends Cell Biol, 2001. 11(10): p. 426‐33.
98. Knebel, A., et al., Dephosphorylation of receptor tyrosine kinases as target of
regulation by radiation, oxidants or alkylating agents. EMBO J, 1996. 15(19): p.
5314‐25.
99. Yoshizumi, M., et al., Src and Cas mediate JNK activation but not ERK1/2 and p38
kinases by reactive oxygen species. J Biol Chem, 2000. 275(16): p. 11706‐12.
100. Moro, L., et al., Integrin‐induced epidermal growth factor (EGF) receptor activation
requires c‐Src and p130Cas and leads to phosphorylation of specific EGF receptor
tyrosines. J Biol Chem, 2002. 277(11): p. 9405‐14.
101. Chen, K., et al., c‐Jun N‐terminal kinase activation by hydrogen peroxide in
endothelial cells involves SRC‐dependent epidermal growth factor receptor
transactivation. J Biol Chem, 2001. 276(19): p. 16045‐50.
102. Biscardi, J.S., et al., c‐Src‐mediated phosphorylation of the epidermal growth factor
receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function.
J Biol Chem, 1999. 274(12): p. 8335‐43.
103. Aikawa, R., et al., Oxidative stress activates extracellular signal‐regulated kinases
through Src and Ras in cultured cardiac myocytes of neonatal rats. J Clin Invest,
1997. 100(7): p. 1813‐21.
104. Tiganis, T., Protein tyrosine phosphatases: dephosphorylating the epidermal
growth factor receptor. IUBMB Life, 2002. 53(1): p. 3‐14.
105. Lee, S.R., et al., Reversible inactivation of protein‐tyrosine phosphatase 1B in A431
cells stimulated with epidermal growth factor. J Biol Chem, 1998. 273(25): p.
15366‐72.
106. Cunnick, J.M., et al., Role of tyrosine kinase activity of epidermal growth factor
receptor in the lysophosphatidic acid‐stimulated mitogen‐activated protein kinase
pathway. J Biol Chem, 1998. 273(23): p. 14468‐75.
107. Wang, X., et al., Epidermal growth factor receptor‐dependent Akt activation by
oxidative stress enhances cell survival. J Biol Chem, 2000. 275(19): p. 14624‐31.
108. Leu, C.M., C. Chang, and C. Hu, Epidermal growth factor (EGF) suppresses
staurosporine‐induced apoptosis by inducing mcl‐1 via the mitogen‐activated
protein kinase pathway. Oncogene, 2000. 19(13): p. 1665‐75.
109. Winograd‐Katz, S.E. and A. Levitzki, Cisplatin induces PKB/Akt activation and
p38(MAPK) phosphorylation of the EGF receptor. Oncogene, 2006. 25(56): p.
7381‐90.
110. Bromberg, J.F., et al., Stat3 as an oncogene. Cell, 1999. 98(3): p. 295‐303.
111. Duan, Z., et al., 8‐benzyl‐4‐oxo‐8‐azabicyclo[3.2.1]oct‐2‐ene‐6,7‐dicarboxylic acid
(SD‐1008), a novel janus kinase 2 inhibitor, increases chemotherapy sensitivity in human ovarian cancer cells. Mol Pharmacol, 2007. 72(5): p. 1137‐45.