Autophagic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer

被引：39
作者：
Lin, Chi-Iou [1 ]
Whang, Edward E. [1 ]
Lorch, Jochen H. [2 ]
Ruan, Daniel T. [1 ]
机构：
[1] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA
[2] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA
来源：
SURGERY | 2012年 / 152卷 / 06期
关键词：
CELL-DEATH; APOPTOSIS; EGFR;
D O I：
10.1016/j.surg.2012.08.016
中图分类号：
R61 [外科手术学];
学科分类号：
摘要：
Background. We hypothesized that autophagy inhibition would enhance the anticancer efficacy of ret protooncogene-targeted therapy in medullary thyroid cancer. Methods. Medullary thyroid cancer-1.1 and TT cells were treated with sunitinib or sorafenib in the presence or absence of everolimus, trehalose, or small interfering RNA directed against autophagy Protein 5. Results. Sunitinib and sorafenib each robustly induced light chain 3-II expression, indicating autophagy activation. Autophagy protein 5 silencing diminished the antiproliferative effects of sunitinib and sorafenib by 44% (P <.05) and 41% (P <.05), respectively, in medullary thyroid cancer-1.1 cells and by 43% <.01) and 39% (P <.05), respectively, in TT cells. In contrast, everolimus increased the antiproliferative effects of sunitinib and sorafenib by 24% (P <.01) and 27% (P <.01), respectively, in medullary thyroid cancer-1.1 cells and by 20% (P <.05) and 23% (P <.05), respectively, in TT cells. Trehalose increased the antiproliferative effects of sunitinib and sorafenib by 26% (P <.01) and 27% (P <.01), respectively, in medullary thyroid cancer-1.1 cells and by 28% (P <.05) and 29% (P <.05), respectively, in TT cells. Autophagy protein 5 silencing abrogated both everolimus and trehalose-induced increases in tyrosine kinase inhibitor efficacy. Conclusion. Loss (gain) of autophagy diminishes (improves) the efficacy of sunitinib and sorafenib. Our findings suggest that autophagic activation should be combined with targeted ret protooncogene therapy for patients with advanced medullary thyroid cancer (Surgery 2012;152:1142-9.)
引用
收藏
页码：1142 / 1149
页数：8
相关论文
共 19 条
[1]   Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells [J].
Bellodi, Cristian ;
Lidonnici, Maria Rosa ;
Hamilton, Ashley ;
Helgason, G. Vignir ;
Soliera, Angela Rachele ;
Ronchetti, Mattia ;
Galavotti, Sara ;
Young, Kenneth W. ;
Selmi, Tommaso ;
Yacobi, Rinat ;
Van Etten, Richard A. ;
Donato, Nick ;
Hunter, Ann ;
Dinsdale, David ;
Tirro, Elena ;
Vigneri, Paolo ;
Nicotera, Pierluigi ;
Dyer, Martin J. ;
Holyoake, Tessa ;
Salomoni, Paolo ;
Calabretta, Bruno .
JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (05) :1109-1123
[2]   Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors [J].
Calabretta, Bruno ;
Salomoni, Paolo .
LEUKEMIA & LYMPHOMA, 2011, 52 :54-59
[3]   Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer:: A 10-year follow-up study [J].
Elisei, Rossella ;
Cosci, Barbara ;
Romei, Cristina ;
Bottici, Valeria ;
Renzini, Giulia ;
Molinaro, Eleonora ;
Agate, Laura ;
Vivaldi, Agnese ;
Faviana, Pinuccia ;
Basolo, Fulvio ;
Miccoli, Paolo ;
Berti, Piero ;
Pacini, Furio ;
Pinchera, Aldo .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2008, 93 (03) :682-687
[4]   Multikinase inhibitors: a new option for the treatment of thyroid cancer [J].
Gild, Matti L. ;
Bullock, Martyn ;
Robinson, Bruce G. ;
Clifton-Bligh, Roderick .
NATURE REVIEWS ENDOCRINOLOGY, 2011, 7 (10) :617-624
[5]   Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST) [J].
Gupta, Anu ;
Roy, Srirupa ;
Lazar, Alexander J. F. ;
Wang, Wei-Lien ;
McAuliffe, John C. ;
Reynoso, David ;
McMahon, James ;
Taguchi, Takahiro ;
Floris, Giuseppe ;
Debiec-Rychter, Maria ;
Schoffski, Patrick ;
Trent, Jonathan A. ;
Debnath, Jayanta ;
Rubin, Brian P. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (32) :14333-14338
[6]   Autophagy Inhibition Enhances Daunorubicin-Induced Apoptosis in K562 Cells [J].
Han, Weidong ;
Sun, Jie ;
Feng, Lifeng ;
Wang, KaiFeng ;
Li, Da ;
Pan, Qin ;
Chen, Yan ;
Jin, Wei ;
Wang, Xian ;
Pan, Hongming ;
Jin, Hongchuan .
PLOS ONE, 2011, 6 (12)
[7]  
Kebebew E, 2000, CANCER-AM CANCER SOC, V88, P1139, DOI 10.1002/(SICI)1097-0142(20000301)88:5<1139::AID-CNCR26>3.0.CO
[8]  
2-Z
[9]   Cell biology - Autophagy as a regulated pathway of cellular degradation [J].
Klionsky, DJ ;
Emr, SD .
SCIENCE, 2000, 290 (5497) :1717-1721
[10]   Autophagy Induction with RAD001 Enhances Chemosensitivity and Radiosensitivity through Met Inhibition in Papillary Thyroid Cancer [J].
Lin, Chi-Iou ;
Whang, Edward E. ;
Donner, David B. ;
Du, Jinyan ;
Lorch, Jochen ;
He, Frank ;
Jiang, Xiaofeng ;
Price, Brendan D. ;
Moore, Francis D., Jr. ;
Ruan, Daniel T. .
MOLECULAR CANCER RESEARCH, 2010, 8 (09) :1217-1226
12