Therapy-resistant Acute Lymphoblastic Leukemia (ALL) Cells Inactivate FOXO3 to Escape Apoptosis Induction by TRAIL and Noxa

Overview

Journal Oncotarget

Specialty Oncology

Date 2013 Jul 6

PMID 23828551

Citations 15

Authors

Michael J Ausserlechner

Christina Salvador

Andrea Deutschmann

Martin Bodner

Giampietro Viola

Roberta Bortolozzi

Giuseppe Basso

Judith Hagenbuchner

Petra Obexer

Affiliations

Soon will be listed here.

Abstract

Forkhead transcription factors (FOXO) are downstream targets of the phosphoinositol-3-kinase (PI3K) protein kinase B (PKB) signaling cascade and play a pivotal role in cell differentiation, cell cycle and apoptosis. We found that cells from prednisone-resistant T-acute lymphoblastic leukemia (T-ALL) patients showed cytoplasmic localization of FOXO3 in comparison to prednisone-sensitive patients suggesting its inactivation. To determine the impact of FOXO3, T-ALL cells were infected with a 4OH-tamoxifen-regulated, phosphorylation-independent FOXO3(A3)ERtm allele. After FOXO3-activation these cells undergo caspase-dependent apoptosis. FOXO3 induces the death ligand TRAIL and the BH3-only protein Noxa implicating extrinsic as well as intrinsic death signaling. Whereas dnFADD partially inhibited cell death, CrmA and dnBID efficiently rescued ALL cells after FOXO3 activation, suggesting a caspase-8 amplifying feedback loop downstream of FADD. Knockdown of TRAIL and Noxa reduced FOXO3-induced apoptosis, implicating that mitochondrial destabilization amplifies TRAIL-signaling. The-reconstitution of the cell cycle inhibitor p16INK4A, which sensitizes ALL cells to mitochondria-induced cell death, represses FOXO3 protein levels and reduces the dependency of these leukemia cells on PI3K-PKB signaling. This suggests that if p16INK4A is deleted during leukemia development, FOXO3 levels elevate and FOXO3 has to be inactivated by deregulation of the PI3K-PKB pathway to prevent FOXO3-induced cell death.

Citing Articles

Identification of as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS).

Faltus C, Lahnsteiner A, Barrdahl M, Assenov Y, Husing A, Bogatyrova O Int J Mol Sci. 2022; 23(18).

PMID: 36142605 PMC: 9505874. DOI: 10.3390/ijms231810699.

Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review).

Yang S, Pang L, Dai W, Wu S, Ren T, Duan Y Front Oncol. 2021; 11:667730.

PMID: 34123834 PMC: 8190381. DOI: 10.3389/fonc.2021.667730.

Critical physiological and pathological functions of Forkhead Box O tumor suppressors.

Dumitrascu G, Bucur O Discoveries (Craiova). 2020; 1(1):e5.

PMID: 32309538 PMC: 6941590. DOI: 10.15190/d.2013.5.

The molecular mechanism of ovarian granulosa cell tumors.

Li J, Bao R, Peng S, Zhang C J Ovarian Res. 2018; 11(1):13.

PMID: 29409506 PMC: 5802052. DOI: 10.1186/s13048-018-0384-1.

miR-708-5p: a microRNA with emerging roles in cancer.

Monteleone N, Lutz C Oncotarget. 2017; 8(41):71292-71316.

PMID: 29050362 PMC: 5642637. DOI: 10.18632/oncotarget.19772.

References

Zhao W . Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways. Leukemia. 2009; 24(1):13-21. DOI: 10.1038/leu.2009.223. View

Tothova Z, Kollipara R, Huntly B, Lee B, Castrillon D, Cullen D . FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007; 128(2):325-39. DOI: 10.1016/j.cell.2007.01.003. View

Mimeault M, Batra S . Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications. Ageing Res Rev. 2008; 8(2):94-112. PMC: 3828651. DOI: 10.1016/j.arr.2008.12.001. View

Tang T, Dowbenko D, Jackson A, Toney L, Lewin D, Dent A . The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor. J Biol Chem. 2002; 277(16):14255-65. DOI: 10.1074/jbc.M110901200. View

Jotta P, Ganazza M, Silva A, Viana M, da Silva M, Zambaldi L . Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia. 2009; 24(1):239-42. DOI: 10.1038/leu.2009.209. View

Seoane J, Le H, Shen L, Anderson S, Massague J . Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004; 117(2):211-23. DOI: 10.1016/s0092-8674(04)00298-3. View

FOLEY G, Lazarus H, Farber S, Uzman B, Boone B, McCarthy R . CONTINUOUS CULTURE OF HUMAN LYMPHOBLASTS FROM PERIPHERAL BLOOD OF A CHILD WITH ACUTE LEUKEMIA. Cancer. 1965; 18:522-9. DOI: 10.1002/1097-0142(196504)18:4<522::aid-cncr2820180418>3.0.co;2-j. View

Essafi A, Fernandez de Mattos S, Hassen Y, Soeiro I, Mufti G, Thomas N . Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene. 2005; 24(14):2317-29. DOI: 10.1038/sj.onc.1208421. View

Yilmaz O, Valdez R, Theisen B, Guo W, Ferguson D, Wu H . Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006; 441(7092):475-82. DOI: 10.1038/nature04703. View

10.

Labi V, Grespi F, Baumgartner F, Villunger A . Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy?. Cell Death Differ. 2008; 15(6):977-87. PMC: 4563920. DOI: 10.1038/cdd.2008.37. View

11.

Obexer P, Hagenbuchner J, Rupp M, Salvador C, Holzner M, Deutsch M . p16INK4A sensitizes human leukemia cells to FAS- and glucocorticoid-induced apoptosis via induction of BBC3/Puma and repression of MCL1 and BCL2. J Biol Chem. 2009; 284(45):30933-40. PMC: 2781493. DOI: 10.1074/jbc.M109.051441. View

12.

Hagenbuchner J, Kuznetsov A, Obexer P, Ausserlechner M . BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene. 2012; 32(40):4748-57. DOI: 10.1038/onc.2012.500. View

13.

Shetty S, Gladden J, Henson E, Hu X, Villanueva J, Haney N . Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkappaB activation in epithelial derived cell lines. Apoptosis. 2002; 7(5):413-20. DOI: 10.1023/a:1020031023947. View

14.

Ausserlechner M, Obexer P, Wiegers G, Hartmann B, Geley S, Kofler R . The cell cycle inhibitor p16(INK4A) sensitizes lymphoblastic leukemia cells to apoptosis by physiologic glucocorticoid levels. J Biol Chem. 2001; 276(24):10984-9. View

15.

Kops G, Medema R, Glassford J, Essers M, Dijkers P, Coffer P . Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol. 2002; 22(7):2025-36. PMC: 133681. DOI: 10.1128/MCB.22.7.2025-2036.2002. View

16.

Gu T, Tothova Z, Scheijen B, Griffin J, Gilliland D, Sternberg D . NPM-ALK fusion kinase of anaplastic large-cell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a. Blood. 2004; 103(12):4622-9. DOI: 10.1182/blood-2003-03-0820. View

17.

Arden K . Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer. Exp Gerontol. 2006; 41(8):709-17. DOI: 10.1016/j.exger.2006.05.015. View

18.

Markman B, Dienstmann R, Tabernero J . Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs. Oncotarget. 2011; 1(7):530-543. PMC: 3248125. DOI: 10.18632/oncotarget.188. View

19.

Paik J, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z . FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007; 128(2):309-23. PMC: 1855089. DOI: 10.1016/j.cell.2006.12.029. View

20.

Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S . Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002; 2(3):183-92. DOI: 10.1016/s1535-6108(02)00127-7. View