Progress of mTOR Signal Pathway in Chemo-Resistance of Gastric Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HU Youlong , JIANG Bojian ,  YU Jiwei.

The First Department of General Surgery， Third People’s Hospital， Shanghai Jiao-Tong University School of Medicine， Shanghai 201999， China;

Corresponding author：

YU Jiwei., Email: jiweiyu919@hotmail.com

Keywords：

Mammalian target of rapamycin; Gastric cancer; Tumor stem cell; Chemo-resistance

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective 　To review the role of mTOR signal pathway in chemo-resistance of gastric cancer.
Methods 　Domestic and international publications related mTOR signal pathway in chemo-resistance of gastric cancer in recent years were collected and reviewed.
Results 　mTOR was a central signaling molecule of mTOR signal pathway， which regulated key cellular processes such as cell growth， cell proliferation， cell metabolism， and angiogenesis. Signaling molecules of mTOR signal pathway were overexpressed in gastric cancer. Moreover， mTOR signal pathway might play an important role in chemo-resistance of gastric cancer， and tumor stem cells were involved in it too.
Conclusion 　As mTOR signal pathway plays an important role in chemo-resistance of gastric cancer， the combination of mTOR inhibitors and chemotherapy drugs may overcome the chemo-resistance of gastric cancer.

Citation： HU Youlong,JIANG Bojian,YU Jiwei.. Progress of mTOR Signal Pathway in Chemo-Resistance of Gastric Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(12): 1352-1356. doi: Copy

1.	Lin Y， Ueda J， Kikuchi S， et al. Comparative epidemiology of gastric cancer between Japan and China[J]. World J Gastroenterol， 2011， 17(39)：4421-4428.
2.	Menges M， Hoehler T. Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction[J].J Cancer Res Clin Oncol， 2009， 135(1)：29-38.
3.	Al-Batran SE， Ducreux M， Ohtsu A. mTOR as a therapeutic target in patients with gastric cancer[J]. Int J Cancer， 2012， 130(3)：491-496.
4.	Wander SA， Hennessy BT， Slingerland JM. Next-generation mTOR inhibitors in clinical oncology：how pathway complexity informs therapeutic strategy[J]. J Clin Invest， 2011， 121(4)：1231-1241.
5.	Sarbassov DD， Ali SM， Sabatini DM. Growing roles for the mTOR pathway[J]. Curr Opin Cell Biol， 2005， 17(6)：596-603.
6.	Yu G， Wang J， Chen Y， et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer[J]. Clin Cancer Res， 2009， 15(5)：1821-1829.
7.	Kamata S， Kishimoto T， Kobayashi S， et al. Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancercells[J]. Cancer Biol Ther， 2007， 6(7)：1036-1043.
8.	Lee KH， Hur HS， Im SA， et al. RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregula-ting thymidylate synthase[J]. Cancer Lett， 2010， 299(1)：22-28.
9.	Semenza GL. HIF-1：upstream and downstream of cancer metab-olism[J]. Curr Opin Genet Dev， 2010， 20(1)：51-56.
10.	Nakamura J， Kitajima Y， Kai K， et al. Hypoxia-inducible factor-1alpha expression predicts the response to 5-fluorouracil-basedadjuvant chemotherapy in advanced gastric cancer[J]. Oncol Rep， 2009， 22(4)：693-699.
11.	Nakamura J， Kitajima Y， Kai K， et al. HIF-1alpha is an unfavor-able determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy[J]. Int J Cancer， 2010， 127(5)：1158-1171.
12.	Rohwer N， Dame C， Haugstetter A， et al. Hypoxia-inducible factor 1α determines gastric cancer chemosensitivity via modulation of p53 and NF-κB[J]. PLoS One， 2010， 5(8)：e12038.
13.	Kim HK， Choi IJ， Kim CG， et al. A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients[J]. PLoS One， 2011， 6(2)：e16694.
14.	姜海广，陆瑞祺，吴巨钢，等. 基质细胞源性因子-1α/CXC趋化因子受体-4轴经PI3K/Akt通路对胃癌细胞CD133表达的调控作用[J]. 中华实验外科杂志， 2012， 29(3)：378-380.
15.	Anderson EC， Hessman C， Levin TG， et al. The role of colorectal cancer stem cells in metastatic disease and therapeutic response[J]. Cancer， 2011， 3(1)：319-339.
16.	Dirks P. Cancer stem cells：invitation to a second round[J].Nature， 2010， 466(7302)：40-41.
17.	Frank NY， Schatton T， Frank MH. The therapeutic promise of the cancer stem cell concept[J]. J Clin Invest， 2010， 120(1)：41-50.
18.	Shafee N， Smith CR， Wei Shuanzeng， et al. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors[J]. Cancer Res， 2008， 68(9)：3243-3250.
19.	To K， Fotovati A， Reipas KM， et al. Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal， mammosphere growth， and drug resistance[J]. Cancer Res， 2010， 70(7)：2840-2851.
20.	Cammareri P， Scopelliti A， Todaro M， et al. Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells[J]. Cancer Res， 2010， 70(11)：4655-4665.
21.	Zhang L， Jiao M， Li L， et al. Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties[J]. J Cancer Res Clin Oncol， 2012， 138(4)：675-686.
22.	Jimeno A， Rudek MA， Kulesza P， et al. Pharmacodynamic-guided modified continuous reassessment method-based， dose-finding study of rapamycin in adult patients with solid tumors[J]. J Clin Oncol， 2008， 26(25)：4172-4179.
23.	Hashimoto I， Koizumi K， Tatematsu M， et al. Blocking on the CXCR4/mTOR signaling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells[J]. Eur J Cancer， 2008， 44(7)：1022-1029.
24.	Cejka D， Preusser M， Fuereder T， et al. mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo[J]. Anticancer Res， 2008， 28(6A)：3801-3808.
25.	Cejka D， Preusser M， Woehrer A， et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo[J]. Cancer Biol Ther， 2008， 7(9)：1377-1385.
26.	Feldman ME， Apsel B， Uotila A， et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2[J]. PLoS Biol， 2009， 7(2)：e1000038.
27.	Choo AY， Yoon SO， Kim SG， et al. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation[J]. Proc Natl Acad Sci U S A， 2008， 105(45)：17414-17419.
28.	Thoreen CC， Kang SA， Chang JW， et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1[J]. J Biol Chem， 2009， 284(12)：8023-8032.
29.	O’reilly KE， Rojo F， She QB， et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt[J]. Cancer Res， 2006， 66(3)：1500-1508.
30.	Breuleux M， Klopfenstein M， Stephan C， et al. Increased Akt S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition[J]. Mol Cancer Ther， 2009， 8(4)：742-753.
31.	García-Martínez JM， Moran J， Clarke RG， et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)[J]. Biochem J， 2009， 421(1)：29-42.
32.	Chresta CM， Davies BR， Hickson I， et al. AZD8055 is a potent， selective， and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity[J]. Cancer Res， 2010， 70(1)：288-298.
33.	Yu K， Shi C， Toral-Barza L， et al. Beyond rapalog therapy：preclinical pharmacology and antitumor activity of WYE-125132， an ATP-competitive and specific inhibitor of mTORC1 and mTORC2[J]. Cancer Res， 2010， 70(2)：621-631.
34.	Bhagwat SV， Gokhale PC， Crew AP， et al. Preclinical characterization of OSI-027， a potent and selective inhibitor of mTORC1 and mTORC2：distinct from rapamycin[J]. Mol Cancer Ther， 2011， 10(8)：1394-1406.
35.	Füreder T， Wanek T， Pflegerl P， et al. BEZ235 impairs gastriccancer growth by inhibition of PI3K/mTOR in vitro and in vivo[J]. BMC Pharmacol， 2010， 10(Suppl 1)：A41.

1. Lin Y， Ueda J， Kikuchi S， et al. Comparative epidemiology of gastric cancer between Japan and China[J]. World J Gastroenterol， 2011， 17(39)：4421-4428.
2. Menges M， Hoehler T. Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction[J].J Cancer Res Clin Oncol， 2009， 135(1)：29-38.
3. Al-Batran SE， Ducreux M， Ohtsu A. mTOR as a therapeutic target in patients with gastric cancer[J]. Int J Cancer， 2012， 130(3)：491-496.
4. Wander SA， Hennessy BT， Slingerland JM. Next-generation mTOR inhibitors in clinical oncology：how pathway complexity informs therapeutic strategy[J]. J Clin Invest， 2011， 121(4)：1231-1241.
5. Sarbassov DD， Ali SM， Sabatini DM. Growing roles for the mTOR pathway[J]. Curr Opin Cell Biol， 2005， 17(6)：596-603.
6. Yu G， Wang J， Chen Y， et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of Chinese patients with gastric cancer[J]. Clin Cancer Res， 2009， 15(5)：1821-1829.
7. Kamata S， Kishimoto T， Kobayashi S， et al. Possible involvement of persistent activity of the mammalian target of rapamycin pathway in the cisplatin resistance of AFP-producing gastric cancercells[J]. Cancer Biol Ther， 2007， 6(7)：1036-1043.
8. Lee KH， Hur HS， Im SA， et al. RAD001 shows activity against gastric cancer cells and overcomes 5-FU resistance by downregula-ting thymidylate synthase[J]. Cancer Lett， 2010， 299(1)：22-28.
9. Semenza GL. HIF-1：upstream and downstream of cancer metab-olism[J]. Curr Opin Genet Dev， 2010， 20(1)：51-56.
10. Nakamura J， Kitajima Y， Kai K， et al. Hypoxia-inducible factor-1alpha expression predicts the response to 5-fluorouracil-basedadjuvant chemotherapy in advanced gastric cancer[J]. Oncol Rep， 2009， 22(4)：693-699.
11. Nakamura J， Kitajima Y， Kai K， et al. HIF-1alpha is an unfavor-able determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy[J]. Int J Cancer， 2010， 127(5)：1158-1171.
12. Rohwer N， Dame C， Haugstetter A， et al. Hypoxia-inducible factor 1α determines gastric cancer chemosensitivity via modulation of p53 and NF-κB[J]. PLoS One， 2010， 5(8)：e12038.
13. Kim HK， Choi IJ， Kim CG， et al. A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients[J]. PLoS One， 2011， 6(2)：e16694.
14. 姜海广，陆瑞祺，吴巨钢，等. 基质细胞源性因子-1α/CXC趋化因子受体-4轴经PI3K/Akt通路对胃癌细胞CD133表达的调控作用[J]. 中华实验外科杂志， 2012， 29(3)：378-380.
15. Anderson EC， Hessman C， Levin TG， et al. The role of colorectal cancer stem cells in metastatic disease and therapeutic response[J]. Cancer， 2011， 3(1)：319-339.
16. Dirks P. Cancer stem cells：invitation to a second round[J].Nature， 2010， 466(7302)：40-41.
17. Frank NY， Schatton T， Frank MH. The therapeutic promise of the cancer stem cell concept[J]. J Clin Invest， 2010， 120(1)：41-50.
18. Shafee N， Smith CR， Wei Shuanzeng， et al. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors[J]. Cancer Res， 2008， 68(9)：3243-3250.
19. To K， Fotovati A， Reipas KM， et al. Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal， mammosphere growth， and drug resistance[J]. Cancer Res， 2010， 70(7)：2840-2851.
20. Cammareri P， Scopelliti A， Todaro M， et al. Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells[J]. Cancer Res， 2010， 70(11)：4655-4665.
21. Zhang L， Jiao M， Li L， et al. Tumorspheres derived from prostate cancer cells possess chemoresistant and cancer stem cell properties[J]. J Cancer Res Clin Oncol， 2012， 138(4)：675-686.
22. Jimeno A， Rudek MA， Kulesza P， et al. Pharmacodynamic-guided modified continuous reassessment method-based， dose-finding study of rapamycin in adult patients with solid tumors[J]. J Clin Oncol， 2008， 26(25)：4172-4179.
23. Hashimoto I， Koizumi K， Tatematsu M， et al. Blocking on the CXCR4/mTOR signaling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells[J]. Eur J Cancer， 2008， 44(7)：1022-1029.
24. Cejka D， Preusser M， Fuereder T， et al. mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo[J]. Anticancer Res， 2008， 28(6A)：3801-3808.
25. Cejka D， Preusser M， Woehrer A， et al. Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo[J]. Cancer Biol Ther， 2008， 7(9)：1377-1385.
26. Feldman ME， Apsel B， Uotila A， et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2[J]. PLoS Biol， 2009， 7(2)：e1000038.
27. Choo AY， Yoon SO， Kim SG， et al. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation[J]. Proc Natl Acad Sci U S A， 2008， 105(45)：17414-17419.
28. Thoreen CC， Kang SA， Chang JW， et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1[J]. J Biol Chem， 2009， 284(12)：8023-8032.
29. O’reilly KE， Rojo F， She QB， et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt[J]. Cancer Res， 2006， 66(3)：1500-1508.
30. Breuleux M， Klopfenstein M， Stephan C， et al. Increased Akt S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition[J]. Mol Cancer Ther， 2009， 8(4)：742-753.
31. García-Martínez JM， Moran J， Clarke RG， et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)[J]. Biochem J， 2009， 421(1)：29-42.
32. Chresta CM， Davies BR， Hickson I， et al. AZD8055 is a potent， selective， and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity[J]. Cancer Res， 2010， 70(1)：288-298.
33. Yu K， Shi C， Toral-Barza L， et al. Beyond rapalog therapy：preclinical pharmacology and antitumor activity of WYE-125132， an ATP-competitive and specific inhibitor of mTORC1 and mTORC2[J]. Cancer Res， 2010， 70(2)：621-631.
34. Bhagwat SV， Gokhale PC， Crew AP， et al. Preclinical characterization of OSI-027， a potent and selective inhibitor of mTORC1 and mTORC2：distinct from rapamycin[J]. Mol Cancer Ther， 2011， 10(8)：1394-1406.
35. Füreder T， Wanek T， Pflegerl P， et al. BEZ235 impairs gastriccancer growth by inhibition of PI3K/mTOR in vitro and in vivo[J]. BMC Pharmacol， 2010， 10(Suppl 1)：A41.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Progress of mTOR Signal Pathway in Chemo-Resistance of Gastric Cancer

Abstract Full text Figures/Tables Video References Cited by

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