Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data
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摘要
BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.
BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.
BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.
引文
1 Giacchetti S,Perpoint B,Zidani R,Le Bail N,Faggiuolo R,Focan C,Chollet P,Llory JF,Letourneau Y,Coudert B,Bertheaut-Cvitkovic F,Larregain-Fournier D,Le Rol A,Walter S,Adam R,Misset JL,Lévi F.Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.J Clin Oncol 2000;18:136-147[PMID:10623704DOI:10.1200/JCO.2000.18.1.136]
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3 Venook AP,Niedzwiecki D,Lenz HJ,Innocenti F,Fruth B,Meyerhardt JA,Schrag D,Greene C,O'Neil BH,Atkins JN,Berry S,Polite BN,O'Reilly EM,Goldberg RM,Hochster HS,Schilsky RL,Bertagnolli MM,El-Khoueiry AB,Watson P,Benson AB,Mulkerin DL,Mayer RJ,Blanke C.Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRASWild-Type Advanced or Metastatic Colorectal Cancer:A Randomized Clinical Trial.JAMA 2017;317:2392-2401[PMID:28632865 DOI:10.1001/jama.2017.7105]
4 Heinemann V,von Weikersthal LF,Decker T,Kiani A,Vehling-Kaiser U,Al-Batran SE,Heintges T,Lerchenmüller C,Kahl C,Seipelt G,Kullmann F,Stauch M,Scheithauer W,Hielscher J,Scholz M,Müller S,Link H,Niederle N,Rost A,H?ffkes HG,Moehler M,Lindig RU,Modest DP,Rossius L,Kirchner T,Jung A,Stintzing S.FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer(FIRE-3):a randomised,open-label,phase 3 trial.Lancet Oncol 2014;15:1065-1075[PMID:25088940 DOI:10.1016/S1470-2045(14)70330-4]
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6 Lièvre A,Bachet JB,Le Corre D,Boige V,Landi B,Emile JF,C?téJF,Tomasic G,Penna C,Ducreux M,Rougier P,Penault-Llorca F,Laurent-Puig P.KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res 2006;66:3992-3995[PMID:16618717 DOI:10.1158/0008-5472.CAN-06-0191]
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9 Zhang J,Yang Z,Xie L,Xu L,Xu D,Liu X.Statins,autophagy and cancer metastasis.Int J Biochem Cell Biol 2013;45:745-752[PMID:23147595 DOI:10.1016/j.biocel.2012.11.001]
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11 Ekstrand AI,J?nsson M,Lindblom A,Borg A,Nilbert M.Frequent alterations of the PI3K/AKT/mTORpathways in hereditary nonpolyposis colorectal cancer.Fam Cancer 2010;9:125-129[PMID:19731079DOI:10.1007/s10689-009-9293-1]
12 Pause A,Belsham GJ,Gingras AC,DonzéO,Lin TA,Lawrence JC,Sonenberg N.Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function.Nature 1994;371:762-767[PMID:7935836 DOI:10.1038/371762a0]
13 Pattingre S,Tassa A,Qu X,Garuti R,Liang XH,Mizushima N,Packer M,Schneider MD,Levine B.Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.Cell 2005;122:927-939[PMID:16179260DOI:10.1016/j.cell.2005.07.002]
14 Wild P,McEwan DG,Dikic I.The LC3 interactome at a glance.J Cell Sci 2014;127:3-9[PMID:24345374 DOI:10.1242/jcs.140426]
15 Weihua Z,Tsan R,Huang WC,Wu Q,Chiu CH,Fidler IJ,Hung MC.Survival of cancer cells is maintained by EGFR independent of its kinase activity.Cancer Cell 2008;13:385-393[PMID:18455122DOI:10.1016/j.ccr.2008.03.015]
16 Guo GF,Jiang WQ,Zhang B,Cai YC,Xu RH,Chen XX,Wang F,Xia LP.Autophagy-related proteins Beclin-1 and LC3 predict cetuximab efficacy in advanced colorectal cancer.World J Gastroenterol 2011;17:4779-4786[PMID:22147978 DOI:10.3748/wjg.v17.i43.4779]
17 Li X,Fan Z.The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex.Cancer Res 2010;70:5942-5952[PMID:20634405 DOI:10.1158/0008-5472.CAN-10-0157]
18 Li X,Lu Y,Pan T,Fan Z.Roles of autophagy in cetuximab-mediated cancer therapy against EGFR.Autophagy 2010;6:1066-1077[PMID:20864811 DOI:10.4161/auto.6.8.13366]
19 Koneri K,Goi T,Hirono Y,Katayama K,Yamaguchi A.Beclin 1 gene inhibits tumor growth in colon cancer cell lines.Anticancer Res 2007;27:1453-1457[PMID:17595761]
20 Alves S,Castro L,Fernandes MS,Francisco R,Castro P,Priault M,Chaves SR,Moyer MP,Oliveira C,Seruca R,C?rte-Real M,Sousa MJ,Preto A.Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy.Oncotarget 2015;6:30787-30802[PMID:26418750 DOI:10.18632/oncotarget.5021]
21 Guo JY,Chen HY,Mathew R,Fan J,Strohecker AM,Karsli-Uzunbas G,Kamphorst JJ,Chen G,Lemons JM,Karantza V,Coller HA,Dipaola RS,Gelinas C,Rabinowitz JD,White E.Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.Genes Dev 2011;25:460-470[PMID:21317241 DOI:10.1101/gad.2016311]
22 Yoshioka A,Miyata H,Doki Y,Yamasaki M,Sohma I,Gotoh K,Takiguchi S,Fujiwara Y,Uchiyama Y,Monden M.LC3,an autophagosome marker,is highly expressed in gastrointestinal cancers.Int J Oncol2008;33:461-468[PMID:18695874]
23 Choi AM,Ryter SW,Levine B.Autophagy in human health and disease.N Engl J Med 2013;368:1845-1846[PMID:23656658 DOI:10.1056/NEJMc1303158]
24 Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation.Cell 2011;144:646-674[PMID:21376230 DOI:10.1016/j.cell.2011.02.013]
25 Gutierrez MG,Master SS,Singh SB,Taylor GA,Colombo MI,Deretic V.Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages.Cell 2004;119:753-766[PMID:15607973 DOI:10.1016/j.cell.2004.11.038]
26 Zou Z,Yuan Z,Zhang Q,Long Z,Chen J,Tang Z,Zhu Y,Chen S,Xu J,Yan M,Wang J,Liu Q.Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells.Autophagy 2012;8:1798-1810[PMID:23026799 DOI:10.4161/auto.22110]
27 Xu N,Zhang J,Shen C,Luo Y,Xia L,Xue F,Xia Q.Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell.Biochem Biophys Res Commun 2012;423:826-831[PMID:22713463 DOI:10.1016/j.bbrc.2012.06.048]
28 Li N,Li X,Li S,Zhou S,Zhou Q.Cisplatin-induced downregulation of SOX1 increases drug resistance by activating autophagy in non-small cell lung cancer cell.Biochem Biophys Res Commun 2013;439:187-190[PMID:23994634 DOI:10.1016/j.bbrc.2013.08.065]
29 Yang M,Zeng P,Kang R,Yu Y,Yang L,Tang D,Cao L.S100A8 contributes to drug resistance by promoting autophagy in leukemia cells.PLoS One 2014;9:e97242[PMID:24820971 DOI:10.1371/journal.pone.0097242]
2 Allegra CJ,Jessup JM,Somerfield MR,Hamilton SR,Hammond EH,Hayes DF,McAllister PK,Morton RF,Schilsky RL.American Society of Clinical Oncology provisional clinical opinion:testing for KRASgene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy.J Clin Oncol 2009;27:2091-2096[PMID:19188670DOI:10.1200/JCO.2009.21.9170]
3 Venook AP,Niedzwiecki D,Lenz HJ,Innocenti F,Fruth B,Meyerhardt JA,Schrag D,Greene C,O'Neil BH,Atkins JN,Berry S,Polite BN,O'Reilly EM,Goldberg RM,Hochster HS,Schilsky RL,Bertagnolli MM,El-Khoueiry AB,Watson P,Benson AB,Mulkerin DL,Mayer RJ,Blanke C.Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRASWild-Type Advanced or Metastatic Colorectal Cancer:A Randomized Clinical Trial.JAMA 2017;317:2392-2401[PMID:28632865 DOI:10.1001/jama.2017.7105]
4 Heinemann V,von Weikersthal LF,Decker T,Kiani A,Vehling-Kaiser U,Al-Batran SE,Heintges T,Lerchenmüller C,Kahl C,Seipelt G,Kullmann F,Stauch M,Scheithauer W,Hielscher J,Scholz M,Müller S,Link H,Niederle N,Rost A,H?ffkes HG,Moehler M,Lindig RU,Modest DP,Rossius L,Kirchner T,Jung A,Stintzing S.FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer(FIRE-3):a randomised,open-label,phase 3 trial.Lancet Oncol 2014;15:1065-1075[PMID:25088940 DOI:10.1016/S1470-2045(14)70330-4]
5 Alan P,Venook DN.Impact of primary(1?°)tumor location on Overall Survival(OS)and Progression Free Survival(PFS)in patients(pts)with metastatic colorectal cancer(mCRC):Analysis of All RAS wt patients on CALGB/SWOG 80405(Alliance)[Abstract].ESMO Congress,2016.
6 Lièvre A,Bachet JB,Le Corre D,Boige V,Landi B,Emile JF,C?téJF,Tomasic G,Penna C,Ducreux M,Rougier P,Penault-Llorca F,Laurent-Puig P.KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res 2006;66:3992-3995[PMID:16618717 DOI:10.1158/0008-5472.CAN-06-0191]
7 Boya P,Reggiori F,Codogno P.Emerging regulation and functions of autophagy.Nat Cell Biol 2013;15:713-720[PMID:23817233 DOI:10.1038/ncb2788]
8 Kenific CM,Thorburn A,Debnath J.Autophagy and metastasis:another double-edged sword.Curr Opin Cell Biol 2010;22:241-245[PMID:19945838 DOI:10.1016/j.ceb.2009.10.008]
9 Zhang J,Yang Z,Xie L,Xu L,Xu D,Liu X.Statins,autophagy and cancer metastasis.Int J Biochem Cell Biol 2013;45:745-752[PMID:23147595 DOI:10.1016/j.biocel.2012.11.001]
10 Johnson SM,Gulhati P,Rampy BA,Han Y,Rychahou PG,Doan HQ,Weiss HL,Evers BM.Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer.J Am Coll Surg 2010;210:767-776,776-778[PMID:20421047 DOI:10.1016/j.jamcollsurg.2009.12.008]
11 Ekstrand AI,J?nsson M,Lindblom A,Borg A,Nilbert M.Frequent alterations of the PI3K/AKT/mTORpathways in hereditary nonpolyposis colorectal cancer.Fam Cancer 2010;9:125-129[PMID:19731079DOI:10.1007/s10689-009-9293-1]
12 Pause A,Belsham GJ,Gingras AC,DonzéO,Lin TA,Lawrence JC,Sonenberg N.Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function.Nature 1994;371:762-767[PMID:7935836 DOI:10.1038/371762a0]
13 Pattingre S,Tassa A,Qu X,Garuti R,Liang XH,Mizushima N,Packer M,Schneider MD,Levine B.Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.Cell 2005;122:927-939[PMID:16179260DOI:10.1016/j.cell.2005.07.002]
14 Wild P,McEwan DG,Dikic I.The LC3 interactome at a glance.J Cell Sci 2014;127:3-9[PMID:24345374 DOI:10.1242/jcs.140426]
15 Weihua Z,Tsan R,Huang WC,Wu Q,Chiu CH,Fidler IJ,Hung MC.Survival of cancer cells is maintained by EGFR independent of its kinase activity.Cancer Cell 2008;13:385-393[PMID:18455122DOI:10.1016/j.ccr.2008.03.015]
16 Guo GF,Jiang WQ,Zhang B,Cai YC,Xu RH,Chen XX,Wang F,Xia LP.Autophagy-related proteins Beclin-1 and LC3 predict cetuximab efficacy in advanced colorectal cancer.World J Gastroenterol 2011;17:4779-4786[PMID:22147978 DOI:10.3748/wjg.v17.i43.4779]
17 Li X,Fan Z.The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1alpha and Bcl-2 and activating the beclin 1/hVps34 complex.Cancer Res 2010;70:5942-5952[PMID:20634405 DOI:10.1158/0008-5472.CAN-10-0157]
18 Li X,Lu Y,Pan T,Fan Z.Roles of autophagy in cetuximab-mediated cancer therapy against EGFR.Autophagy 2010;6:1066-1077[PMID:20864811 DOI:10.4161/auto.6.8.13366]
19 Koneri K,Goi T,Hirono Y,Katayama K,Yamaguchi A.Beclin 1 gene inhibits tumor growth in colon cancer cell lines.Anticancer Res 2007;27:1453-1457[PMID:17595761]
20 Alves S,Castro L,Fernandes MS,Francisco R,Castro P,Priault M,Chaves SR,Moyer MP,Oliveira C,Seruca R,C?rte-Real M,Sousa MJ,Preto A.Colorectal cancer-related mutant KRAS alleles function as positive regulators of autophagy.Oncotarget 2015;6:30787-30802[PMID:26418750 DOI:10.18632/oncotarget.5021]
21 Guo JY,Chen HY,Mathew R,Fan J,Strohecker AM,Karsli-Uzunbas G,Kamphorst JJ,Chen G,Lemons JM,Karantza V,Coller HA,Dipaola RS,Gelinas C,Rabinowitz JD,White E.Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis.Genes Dev 2011;25:460-470[PMID:21317241 DOI:10.1101/gad.2016311]
22 Yoshioka A,Miyata H,Doki Y,Yamasaki M,Sohma I,Gotoh K,Takiguchi S,Fujiwara Y,Uchiyama Y,Monden M.LC3,an autophagosome marker,is highly expressed in gastrointestinal cancers.Int J Oncol2008;33:461-468[PMID:18695874]
23 Choi AM,Ryter SW,Levine B.Autophagy in human health and disease.N Engl J Med 2013;368:1845-1846[PMID:23656658 DOI:10.1056/NEJMc1303158]
24 Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation.Cell 2011;144:646-674[PMID:21376230 DOI:10.1016/j.cell.2011.02.013]
25 Gutierrez MG,Master SS,Singh SB,Taylor GA,Colombo MI,Deretic V.Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages.Cell 2004;119:753-766[PMID:15607973 DOI:10.1016/j.cell.2004.11.038]
26 Zou Z,Yuan Z,Zhang Q,Long Z,Chen J,Tang Z,Zhu Y,Chen S,Xu J,Yan M,Wang J,Liu Q.Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells.Autophagy 2012;8:1798-1810[PMID:23026799 DOI:10.4161/auto.22110]
27 Xu N,Zhang J,Shen C,Luo Y,Xia L,Xue F,Xia Q.Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell.Biochem Biophys Res Commun 2012;423:826-831[PMID:22713463 DOI:10.1016/j.bbrc.2012.06.048]
28 Li N,Li X,Li S,Zhou S,Zhou Q.Cisplatin-induced downregulation of SOX1 increases drug resistance by activating autophagy in non-small cell lung cancer cell.Biochem Biophys Res Commun 2013;439:187-190[PMID:23994634 DOI:10.1016/j.bbrc.2013.08.065]
29 Yang M,Zeng P,Kang R,Yu Y,Yang L,Tang D,Cao L.S100A8 contributes to drug resistance by promoting autophagy in leukemia cells.PLoS One 2014;9:e97242[PMID:24820971 DOI:10.1371/journal.pone.0097242]