Neurotensin Receptor Type 2 Protects B-cell Chronic Lymphocytic Leukemia Cells from Apoptosis

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2017 Oct 24

PMID 29059151

Citations 10

Authors

A Abbaci

H Talbot

S Saada

N Gachard

J Abraham

A Jaccard

D Bordessoule

A L Fauchais

T Naves

M O Jauberteau

Affiliations

Soon will be listed here.

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) cells are resistant to apoptosis, and consequently accumulate to the detriment of normal B cells and patient immunity. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors drives cell transformation, and thus plays a critical role in malignancies. In this study, we identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed in B-CLL cells, whereas expression of its natural ligand, neurotensin (NTS), was minimal in both B-CLL cells and patient plasma. Surprisingly, NTSR2 remained in a constitutively active phosphorylated state, caused not by a mutation-induced gain-of-function but rather by an interaction with the oncogenic tyrosine kinase receptor TrkB. Functional and biochemical characterization revealed that the NTSR2-TrkB interaction acts as a conditional oncogenic driver requiring the TrkB ligand brain-derived neurotrophic factor (BDNF), which unlike NTS is highly expressed in B-CLL cells. Together, NTSR2, TrkB and BDNF induce autocrine and/or paracrine survival pathways that are independent of mutation status and indolent or progressive disease course. The NTSR2-TrkB interaction activates survival signaling pathways, including the Src and AKT kinase pathways, as well as expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. When NTSR2 was downregulated, TrkB failed to protect B-CLL cells from a drastic decrease in viability via typical apoptotic cell death, reflected by DNA fragmentation and Annexin V presentation. Together, our findings demonstrate that the NTSR2-TrkB interaction plays a crucial role in B-CLL cell survival, suggesting that inhibition of NTSR2 represents a promising targeted strategy for treating B-CLL malignancy.

Citing Articles

Extracellular vesicles from type-2 macrophages increase the survival of chronic lymphocytic leukemia cells ex vivo.

Ikhlef L, Ratti N, Durand S, Formento R, Daverat H, Boutaud M Cancer Gene Ther. 2024; 31(8):1164-1176.

PMID: 38918490 PMC: 11327105. DOI: 10.1038/s41417-024-00802-7.

Targeting the NTSR2/TrkB oncogenic pathway in chronic lymphocytic leukemia.

Ikhlef L, Yassine M, Chandouri B, Riviere L, Naves T, Dmytruk N Sci Rep. 2024; 14(1):6084.

PMID: 38480783 PMC: 10937676. DOI: 10.1038/s41598-024-56663-5.

The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia.

Cerreto M, Foa R, Natoni A Cancers (Basel). 2023; 15(21).

PMID: 37958334 PMC: 10647257. DOI: 10.3390/cancers15215160.

miR-603 promotes cell proliferation and differentiation by targeting TrkB in acute promyelocytic leukemia.

Li H, Hou J, Fu Y, Zhao Y, Liu J, Guo D Ann Hematol. 2023; 102(12):3357-3367.

PMID: 37726492 DOI: 10.1007/s00277-023-05441-w.

Design, Synthesis, and Biological Evaluation of the First Radio-Metalated Neurotensin Analogue Targeting Neurotensin Receptor 2.

Bodin S, Previti S, Jestin E, Vimont D, Ait-Arsa I, Lamare F ACS Omega. 2023; 8(7):6994-7004.

PMID: 36844603 PMC: 9948202. DOI: 10.1021/acsomega.2c07814.

References

Vita N, Oury-Donat F, Chalon P, Guillemot M, Kaghad M, Bachy A . Neurotensin is an antagonist of the human neurotensin NT2 receptor expressed in Chinese hamster ovary cells. Eur J Pharmacol. 1998; 360(2-3):265-72. DOI: 10.1016/s0014-2999(98)00678-5. View

Cattaneo F, Guerra G, Parisi M, De Marinis M, Tafuri D, Cinelli M . Cell-surface receptors transactivation mediated by g protein-coupled receptors. Int J Mol Sci. 2014; 15(11):19700-28. PMC: 4264134. DOI: 10.3390/ijms151119700. View

Ohman L, Franzen L, Rudolph U, Birnbaumer L, Hornquist E . Regression of Peyer's patches in G alpha i2 deficient mice prior to colitis is associated with reduced expression of Bcl-2 and increased apoptosis. Gut. 2002; 51(3):392-7. PMC: 1773369. DOI: 10.1136/gut.51.3.392. View

Thiele C, Li Z, McKee A . On Trk--the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res. 2009; 15(19):5962-7. PMC: 2756331. DOI: 10.1158/1078-0432.CCR-08-0651. View

Magazin M, Poszepczynska-Guigne E, Bagot M, Boumsell L, Pruvost C, Chalon P . Sezary syndrome cells unlike normal circulating T lymphocytes fail to migrate following engagement of NT1 receptor. J Invest Dermatol. 2004; 122(1):111-8. DOI: 10.1046/j.0022-202X.2003.22131.x. View

El-Shewy H, Johnson K, Lee M, Jaffa A, Obeid L, Luttrell L . Insulin-like growth factors mediate heterotrimeric G protein-dependent ERK1/2 activation by transactivating sphingosine 1-phosphate receptors. J Biol Chem. 2006; 281(42):31399-407. DOI: 10.1074/jbc.M605339200. View

Schrottner P, Leick M, Burger M . The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact. Ann Hematol. 2009; 89(5):437-46. DOI: 10.1007/s00277-009-0876-6. View

Mazella J, Zsurger N, Navarro V, Chabry J, Kaghad M, Caput D . The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J Biol Chem. 1998; 273(41):26273-6. DOI: 10.1074/jbc.273.41.26273. View

Ghosh A, Kay N . Critical signal transduction pathways in CLL. Adv Exp Med Biol. 2013; 792:215-39. PMC: 3918736. DOI: 10.1007/978-1-4614-8051-8_10. View

10.

Ai L, Sun C, Wang Y, Zhang L, Chu Z, Qin Y . Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo. Int J Cancer. 2013; 133(5):1074-84. DOI: 10.1002/ijc.28116. View

11.

Kehrl J . The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity. Biochem Pharmacol. 2016; 114:40-52. PMC: 4993105. DOI: 10.1016/j.bcp.2016.04.005. View

12.

Pearse R, Swendeman S, Li Y, Rafii D, Hempstead B . A neurotrophin axis in myeloma: TrkB and BDNF promote tumor-cell survival. Blood. 2005; 105(11):4429-36. DOI: 10.1182/blood-2004-08-3096. View

13.

Kitada S, Andersen J, Akar S, Zapata J, Takayama S, Krajewski S . Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. Blood. 1998; 91(9):3379-89. View

14.

Dupouy S, Mourra N, Doan V, Gompel A, Alifano M, Forgez P . The potential use of the neurotensin high affinity receptor 1 as a biomarker for cancer progression and as a component of personalized medicine in selective cancers. Biochimie. 2011; 93(9):1369-78. DOI: 10.1016/j.biochi.2011.04.024. View

15.

Delcourt N, Bockaert J, Marin P . GPCR-jacking: from a new route in RTK signalling to a new concept in GPCR activation. Trends Pharmacol Sci. 2007; 28(12):602-7. DOI: 10.1016/j.tips.2007.09.007. View

16.

Choi S, Chae H, Park T, Ha H, Kim K . Characterization of high affinity neurotensin receptor NTR1 in HL-60 cells and its down regulation during granulocytic differentiation. Br J Pharmacol. 1999; 126(4):1050-6. PMC: 1571214. DOI: 10.1038/sj.bjp.0702378. View

17.

Frade J, Rodriguez-Tebar A, Barde Y . Induction of cell death by endogenous nerve growth factor through its p75 receptor. Nature. 1996; 383(6596):166-8. DOI: 10.1038/383166a0. View

18.

Strober W . Trypan Blue Exclusion Test of Cell Viability. Curr Protoc Immunol. 2015; 111:A3.B.1-A3.B.3. PMC: 6716531. DOI: 10.1002/0471142735.ima03bs111. View

19.

Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas J, Sanchez A, Martin-Saavedra F . A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia. 2004; 18(8):1391-400. DOI: 10.1038/sj.leu.2403398. View

20.

Chiorazzi N, Rai K, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med. 2005; 352(8):804-15. DOI: 10.1056/NEJMra041720. View