Klotho, an Anti-aging Gene, Acts As a Tumor Suppressor and Inhibitor of IGF-1R Signaling in Diffuse Large B Cell Lymphoma

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2017 Feb 4

PMID 28153033

Citations 31

Authors

Xiangxiang Zhou

Xiaosheng Fang

Yujie Jiang

Lingyun Geng

Xinyu Li

Ying Li

Kang Lu

Peipei Li

Xiao Lv

Xin Wang

Affiliations

Soon will be listed here.

Abstract

Background: Klotho, is a transmembrane protein, performs as a circulating hormone and upstream modulator of the insulin-like growth factor-1 receptor (IGF-1R), fibroblast growth factor (FGF), and Wnt signaling pathways. These pathways are involved in the development and progression of B cell lymphoma. We aimed to explore the expression pattern and functional mechanism of Klotho in diffuse large B cell lymphoma (DLBCL).

Methods: Immunohistochemistry (IHC) and western blotting were performed to detect the expression level of Klotho in DLBCL patients and cell lines. Tumor suppressive effect of Klotho was determined by both in vitro and in vivo studies. Signaling pathway activity was assessed by western blotting.

Results: Remarkable lower expression levels of Klotho were observed in DLBCL patients and cell lines. Enforced expression of Klotho could significantly induce cell apoptosis and inhibit tumor growth in DLBCL. Upregulation of Klotho resulted in declined activation of IGF-1R signaling, accompanied with decreased phosphorylation of its downstream targets, including AKT and ERK1/2. Moreover, xenograft model treated with either Klotho overexpression vector or recombinant human Klotho administration presented restrained tumor growth and lower Ki67 staining.

Conclusions: Our findings establish that Klotho performs as a tumor suppressor and modulator of IGF-1R signaling in DLBCL. Targeting Klotho may provide novel strategies for future therapeutic intervention.

Citing Articles

Klotho enhances stability of chronic kidney disease atherosclerotic plaques by inhibiting GRK2/PLC-β-mediated endoplasmic reticulum stress in macrophages via modulation of the ROS/SHP1 pathway.

Li Z, Li J, Li L, Wang Q, Zhang Q, Tian L Sci Rep. 2024; 14(1):32091.

PMID: 39738381 PMC: 11685394. DOI: 10.1038/s41598-024-83596-w.

NCAPD3 promotes diffuse large B-cell lymphoma progression through modulating SIRT1 expression in an H3K9 monomethylation-dependent manner.

Lu T, Yang J, Cai Y, Ding M, Yu Z, Fang X J Adv Res. 2024; 68:163-178.

PMID: 38432395 PMC: 11785590. DOI: 10.1016/j.jare.2024.02.024.

Exogenous Klotho Extends Survival in COVID-19 Model Mice.

Alem F, Campos-Obando N, Narayanan A, Bailey C, Macaya R Pathogens. 2023; 12(12).

PMID: 38133288 PMC: 10746004. DOI: 10.3390/pathogens12121404.

Targeting YTHDF2 inhibits tumorigenesis of diffuse large B-cell lymphoma through ACER2-mediated ceramide catabolism.

Chen X, Lu T, Ding M, Cai Y, Yu Z, Zhou X J Adv Res. 2023; 63:17-33.

PMID: 37865189 PMC: 11379987. DOI: 10.1016/j.jare.2023.10.010.

PKC regulates αKlotho gene expression in MDCK and NRK-52E cells.

Wolf L, Vogt J, Alber J, Franjic D, Feger M, Foller M Pflugers Arch. 2023; 476(1):75-86.

PMID: 37773536 PMC: 10758369. DOI: 10.1007/s00424-023-02863-3.

References

Ligumsky H, Rubinek T, Merenbakh-Lamin K, Yeheskel A, Sertchook R, Shahmoon S . Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure-Function Analysis. Mol Cancer Res. 2015; 13(10):1398-407. DOI: 10.1158/1541-7786.MCR-15-0141. View

Stromberg T, Feng X, Delforoush M, Berglund M, Lin Y, Axelson M . Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells. Med Oncol. 2015; 32(7):188. DOI: 10.1007/s12032-015-0630-y. View

Tilly H, Gomes Da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A . Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v116-25. DOI: 10.1093/annonc/mdv304. View

Lam B, Dai L, Qin Z . The role of HGF/c-MET signaling pathway in lymphoma. J Hematol Oncol. 2016; 9(1):135. PMC: 5141645. DOI: 10.1186/s13045-016-0366-y. View

Xie B, Zhou J, Yuan L, Ren F, Liu D, Li Q . Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Hum Pathol. 2012; 44(5):795-801. DOI: 10.1016/j.humpath.2012.07.023. View

Li X, Huang L, Peng J, Liang L, Shi D, Zheng H . Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway. Int J Oncol. 2014; 45(2):611-8. DOI: 10.3892/ijo.2014.2430. View

Kuro-O M . Klotho. Pflugers Arch. 2009; 459(2):333-43. DOI: 10.1007/s00424-009-0722-7. View

Szczuraszek K, Mazur G, Jelen M, Dziegiel P, Surowiak P, Zabel M . Prognostic significance of Ki-67 antigen expression in non-Hodgkin's lymphomas. Anticancer Res. 2008; 28(2A):1113-8. View

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T . Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997; 390(6655):45-51. DOI: 10.1038/36285. View

10.

Martelli M, Ferreri A, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri S . Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013; 87(2):146-71. DOI: 10.1016/j.critrevonc.2012.12.009. View

11.

Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A . Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat. 2011; 133(2):649-57. DOI: 10.1007/s10549-011-1824-4. View

12.

Herrero-Sanchez M, Rodriguez-Serrano C, Almeida J, San Segundo L, Inoges S, Santos-Briz A . Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development. J Hematol Oncol. 2016; 9(1):113. PMC: 5072323. DOI: 10.1186/s13045-016-0343-5. View

13.

McCubrey J, Steelman L, Bertrand F, Davis N, Abrams S, Montalto G . Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia. 2013; 28(1):15-33. PMC: 3887408. DOI: 10.1038/leu.2013.184. View

14.

Roberts P, Der C . Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007; 26(22):3291-310. DOI: 10.1038/sj.onc.1210422. View

15.

Sun H, Gao Y, Lu K, Zhao G, Li X, Li Z . Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World J Surg Oncol. 2015; 13:307. PMC: 4619481. DOI: 10.1186/s12957-015-0717-0. View

16.

Lee J, Jeong D, Kim J, Lee S, Park J, Chang B . The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Mol Cancer. 2010; 9:109. PMC: 2885346. DOI: 10.1186/1476-4598-9-109. View

17.

Gigante M, Lucarelli G, Divella C, Netti G, Pontrelli P, Cafiero C . Soluble Serum αKlotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma. Medicine (Baltimore). 2015; 94(45):e1917. PMC: 4912252. DOI: 10.1097/MD.0000000000001917. View

18.

Sehn L, Gascoyne R . Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2014; 125(1):22-32. DOI: 10.1182/blood-2014-05-577189. View

19.

Yaktapour N, Ubelhart R, Schuler J, Aumann K, Dierks C, Burger M . Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia. Blood. 2013; 122(9):1621-33. DOI: 10.1182/blood-2013-02-484386. View

20.

Toffalini F, Demoulin J . New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases. Blood. 2010; 116(14):2429-37. DOI: 10.1182/blood-2010-04-279752. View