|
|
|
| Regulation of SIRT1 in acquired resistance of TKIs in non-small cell lung cancer |
| LI Guifang1 YUAN Xiang2 LIU Yiwen2 MA Mingyang1 SUN Jiangtao3 |
1.First Affiliated Hospital, College of Clinical Medicine of He′nan University of Science and Technology, He′nan Province, Luoyang 471003, China;
2.He′nan Key Laboratory of Cancer Epigenetics Cancer Institute, the First Affiliated Hospital of He′nan University of Science and Technology, He′nan Province, Luoyang 471003, China;
3.The First Affiliated Hospital of He′nan University of Science and Technology, He′nan Province, Luoyang 471003, China |
|
|
|
Abstract Objective To analyze the regulation of histone deacetylase SIRT1 in stem cell-like properties of non-small cell lung cancer. Methods The percentage of tumor stem cells was detected by flow cytometry in PC-9 and PC-9-GR cell lines; IC50 was detected by CCK8; SIRT1 mRNA expression was detected by qPCR; SIRT1 protein expression was detected by Western blot; the experiments of cell suspension cloning into spheres was used to detect the capability of sphere-forming of different groups. Results The drug-resistant cell line PC-9-GR was successfully established. The IC50, ALDHbright tumor stem cell percentage, SIRT1 protein expression and SIRT1 mRNA expression of PC-9-GR were higher than those of PC-9 (P < 0.05). The experiments of cell suspension cloning into spheres found that PC-9-GR was significantly higher than PC-9 (P < 0.05), and the effect of PC-9-GR on the capability of sphere-forming was not statistically significant after the application of Gefitinib (P > 0.05). After the combination of SIRT1 specific inhibitor TV6 and double drug combination, the capability of sphere-forming of the two cell lines was significantly lower than that of the control group (P < 0.05). Conclusions Acquired resistance to tyrosine kinase inhibitors in non-small cell lung cancer is closely related to the enrichment of ALDH1+ labeled cancer stem cells by tyrosine kinase inhibitors. Histone deacetylase SIRT1 plays an important role in maintaining the stem of these cancer stem cells. Its inhibition of SIRT1 targeting tumor stem cells may help delay the acquired resistance of tyrosine kinase inhibitors.
|
|
|
|
|
|
[1] Mok TS，Wu YL，Thongprasert S，et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma [J]. N Engl J Med，2009，361（10）：947.
[2] Singh A，Settleman J. EMT，cancer stem cells and drug resistance：an emerging axis of evil in the war on cancer [J]. Oncogene，2010，29（34）：4741-4751.
[3] Jiang F. Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer [J]. Mol Cancer Res，2009，7（3）：330-338.
[4] Marcato P，Dean CA，Pan D，et al. Aldehyde Dehydrogenase Activity of Breast Cancer Stem Cells Is Primarily Due To Isoform ALDH1A3 and Its Expression Is Predictive of Metastasis [J]. Stem Cells，2011，29（1）：32-45.
[5] Luo Y，Dallaglio K，Chen Y，et al. ALDH1A Isozymes are Markers of Human Melanoma Stem Cells and Potential Therapeutic Targets [J]. Stem Cells （Miamisburg），2012， 30（10）：2100-2113.
[6] Sullivan JP，Spinola M，Dodge M，et al. Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling [J]. Cancer Res，2010， 70（23）：9937-9948.
[7] Kim IG，Kim SY，Choi SI，et al. Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling [J]. Oncogene，2014，33（30）：3908-3917.
[8] Arasada RR，Amann JM，Rahman MA，et al. EGFR Blockade Enriches for Lung Cancer Stem-like Cells through Notch3-Dependent Signaling [J]. Cancer Res，2014， 74（19）：5572-5584.
[9] de Aberasturi AL，Redrado M，Villalba M，et al. TMPRSS4 induces cancer stem cell-like properties in lung cancer cells and correlates with ALDH expression in NSCLC patients [J]. Cancer Letters，2016，370（2）：165-176.
[10] Wang Z，Chen W. Emerging Roles of SIRT1 in Cancer Drug Resistance [J]. Genes Cancer，2013，4（3/4）：82-90.
[11] Shien K，Toyooka S，Yamamoto H，et al. Acquired Resistance to EGFR Inhibitors Is Associated with a Manifestation of Stem Cell-like Properties in Cancer Cells [J]. Cancer Res，2013，73（10）：3051-3061.
[12] J?覿nne PA. Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours [J]. Lung Cancer，2008， 60 Suppl 2：S3-S9.
[13] Bai XY，Zhang XC，Yang SQ，et al. Blockade of Hedgehog Signaling Synergistically Increases Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Cell Lines [J]. PLos One，2016，11（3）：e0149370.
[14] Morgillo F，Amendola G，Della Corte CM，et al. Dual MET and SMO negative modulators overcome resistance to EGFR inhibitors in human non-small cell lung cancer [J]. J Med Chem，2017，60（17）：7447-7458.
[15] Bora-Singhal N，Perumal D，Nguyen J，et al. Gli1-Mediated Regulation of Sox2 Facilitates Self-Renewal of Stem-Like Cells and Confers Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer [J]. Neoplasia，2015，17（7）：538-551.
[16] Cheng J，Yang K，Zhang Q，et al. The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner [J]. Sci Rep，2016，6（1）：16993.
[17] Ichihara E，Westover D，Meador CB，et al. SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer [J]. Cancer Res，2017，77（11）：2990-3000.
[18] Li H. Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Patients with/without EGFR-Mutation：Evidence Based on Recent Phase Ⅲ Randomized Trials [J]. Med Sci Monit，2014，20：2666-2676.
[19] Cappuzzo F，Ciuleanu T，Stelmakh L，et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer：A multicentre，randomised，placebo-controlled phase 3 study [J]. Lancet Oncol，2010，11（6）：521-529.
[20] Yang H，Bi Y，Xue L，et al. Multifaceted Modulation of SIRT1 in Cancer and Inflammation [J]. Crit Rev Oncog，2015，20（1/2）：49-64.
[21] Raffaele P，Mauro C，David DM，et al. Sirtuins and Cancer：Role in the Epithelial-Mesenchymal Transition [J]. Oxid Med Cell Longev，2016，2016：1-9.
[22] Li L，Osdal T，Ho Y，et al. SIRT1 Activation by a c-MYC Oncogenic Network Promotes the Maintenance and Drug Resistance of Human FLT3-ITD Acute Myeloid Leukemia Stem Cells [J]. Cell Stem Cell，2014，15（4）：431-446.
[23] Zeisig B，So C. A Knockout Combo：Eradicating AML Stem Cells with TKI plus SIRT1 Inhibition [J]. Cell Stem Cell，2014，15（4）：395-397.
[24] Zhang W，Gao C，Konopleva M，et al. Reversal of Acquired Drug Resistance in FLT3-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies [J]. Clin Cancer Res，2014，20（9）：2363-2374.
[25] Powell MJ，Casimiro MC，Carlos CC，et al. Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation [J]. Cancer Res，2011，71（3）：964-975. |
|
|
|
