Elevated Calpain Activity in Acute Myelogenous Leukemia Correlates with Decreased Calpastatin Expression

Overview

Journal Blood Cancer J

Date 2012 Jul 26

PMID 22829235

Citations 7

Authors

M Niapour

C Farr

M Minden

S A Berger

Affiliations

Soon will be listed here.

Abstract

Calpains are intracellular cysteine proteases that have crucial roles in many physiological and pathological processes. Elevated calpain activity has been associated with many pathological states. Calpain inhibition can be protective or lethal depending on the context. Previous work has shown that c-myc transformation regulates calpain activity by suppressing calpastatin, the endogenous negative regulator of calpain. Here, we have investigated calpain activity in primary acute myelogenous leukemia (AML) blast cells. Calpain activity was heterogeneous and greatly elevated over a wide range in AML blast cells, with no correlation to FAB classification. Activity was particularly elevated in the CD34+CD38- enriched fraction compared with the CD34+CD38+ fraction. Treatment of the cells with the specific calpain inhibitor, PD150606, induced significant apoptosis in AML blast cells but not in normal equivalent cells. Sensitivity to calpain inhibition correlated with calpain activity and preferentially targeted CD34+CD38- cells. There was no correlation between calpain activity and p-ERK levels, suggesting the ras pathway may not be a major contributor to calpain activity in AML. A significant negative correlation existed between calpain activity and calpastatin, suggesting calpastatin is the major regulator of activity in these cells. Analysis of previously published microarray data from a variety of AML patients demonstrated a significant negative correlation between calpastatin and c-myc expression. Patients who achieved a complete remission had significantly lower calpain activity than those who had no response to treatment. Taken together, these results demonstrate elevated calpain activity in AML, anti-leukemic activity of calpain inhibition and prognostic potential of calpain activity measurement.

Citing Articles

Testing calpain inhibition in tumor endothelial cells: novel targetable biomarkers against glioblastoma malignancy.

Guarnaccia L, Navone S, Begani L, Barilla E, Garzia E, Campanella R Front Oncol. 2024; 14:1355202.

PMID: 39156707 PMC: 11327812. DOI: 10.3389/fonc.2024.1355202.

Transcriptomic comparison of bone marrow CD34 + cells and peripheral blood neutrophils from ET patients with JAK2 or CALR mutations.

Guijarro-Hernandez A, Vizmanos J BMC Genom Data. 2023; 24(1):40.

PMID: 37550636 PMC: 10408115. DOI: 10.1186/s12863-023-01142-5.

Changes in calpain-2 expression during glioblastoma progression predisposes tumor cells to temozolomide resistance by minimizing DNA damage and p53-dependent apoptosis.

Stillger M, Chen C, Lai Z, Li M, Schafer A, Pagenstecher A Cancer Cell Int. 2023; 23(1):49.

PMID: 36932402 PMC: 10022304. DOI: 10.1186/s12935-023-02889-8.

The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome.

Brenner A, Aasebo E, Hernandez-Valladares M, Selheim F, Berven F, Gronningsaeter I Cancers (Basel). 2019; 11(1).

PMID: 30634713 PMC: 6356272. DOI: 10.3390/cancers11010073.

Calpastatin phosphorylation regulates radiation-induced calpain activity in glioblastoma.

Bassett E, Palanichamy K, Pearson M, McElroy J, Haque S, Bell E Oncotarget. 2018; 9(18):14597-14607.

PMID: 29581866 PMC: 5865692. DOI: 10.18632/oncotarget.24523.

References

Vermaelen M, Sirvent P, Raynaud F, Astier C, Mercier J, Lacampagne A . Differential localization of autolyzed calpains 1 and 2 in slow and fast skeletal muscles in the early phase of atrophy. Am J Physiol Cell Physiol. 2006; 292(5):C1723-31. DOI: 10.1152/ajpcell.00398.2006. View

Gutierrez N, Lopez-Perez R, Hernandez J, Isidro I, Gonzalez B, Delgado M . Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. Leukemia. 2005; 19(3):402-9. DOI: 10.1038/sj.leu.2403625. View

Hirano M, Osada S, Aoki T, Hirai S, Hosaka M, Inoue J . MEK kinase is involved in tumor necrosis factor alpha-induced NF-kappaB activation and degradation of IkappaB-alpha. J Biol Chem. 1996; 271(22):13234-8. DOI: 10.1074/jbc.271.22.13234. View

Yang P, Chen H, Tsai J, Lin L . Cadmium induces Ca2+-dependent necrotic cell death through calpain-triggered mitochondrial depolarization and reactive oxygen species-mediated inhibition of nuclear factor-kappaB activity. Chem Res Toxicol. 2007; 20(3):406-15. DOI: 10.1021/tx060144c. View

Sasaki T, Kikuchi T, Yumoto N, Yoshimura N, Murachi T . Comparative specificity and kinetic studies on porcine calpain I and calpain II with naturally occurring peptides and synthetic fluorogenic substrates. J Biol Chem. 1984; 259(20):12489-94. View

Dicato M, Boccadoro M, Cavenagh J, Harousseau J, Ludwig H, San Miguel J . Management of multiple myeloma with bortezomib: experts review the data and debate the issues. Oncology. 2007; 70(6):474-82. DOI: 10.1159/000099284. View

Samantaray S, Ray S, Ali S, Banik N . Calpain activation in apoptosis of motoneurons in cell culture models of experimental parkinsonism. Ann N Y Acad Sci. 2006; 1074:349-56. DOI: 10.1196/annals.1369.034. View

Wang K, Nath R, Posner A, Raser K, Hajimohammadreza I, Probert A Jr W . An alpha-mercaptoacrylic acid derivative is a selective nonpeptide cell-permeable calpain inhibitor and is neuroprotective. Proc Natl Acad Sci U S A. 1996; 93(13):6687-92. PMC: 39087. DOI: 10.1073/pnas.93.13.6687. View

Soboloff J, Zhang Y, Minden M, Berger S . Sensitivity of myeloid leukemia cells to calcium influx blockade: application to bone marrow purging. Exp Hematol. 2002; 30(10):1219-26. DOI: 10.1016/s0301-472x(02)00893-7. View

10.

Frohling S, Scholl C, Gilliland D, Levine R . Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol. 2005; 23(26):6285-95. DOI: 10.1200/JCO.2005.05.010. View

11.

Betts R, Anagli J . The beta- and gamma-CH2 of B27-WT's Leu11 and Ile18 side chains play a direct role in calpain inhibition. Biochemistry. 2004; 43(9):2596-604. DOI: 10.1021/bi0359832. View

12.

Hassen G, Feliberti J, Kesner L, Stracher A, Mokhtarian F . A novel calpain inhibitor for the treatment of acute experimental autoimmune encephalomyelitis. J Neuroimmunol. 2006; 180(1-2):135-46. DOI: 10.1016/j.jneuroim.2006.08.005. View

13.

Stifanese R, Averna M, Salamino F, Cantoni C, Mingari M, Prato C . Characterization of the calpain/calpastatin system in human hemopoietic cell lines. Arch Biochem Biophys. 2006; 456(1):48-57. DOI: 10.1016/j.abb.2006.09.022. View

14.

Zhu W, Murtha P, Young C . Calpain inhibitor-induced apoptosis in human prostate adenocarcinoma cells. Biochem Biophys Res Commun. 1995; 214(3):1130-7. DOI: 10.1006/bbrc.1995.2403. View

15.

Kim K, Lee Y, Shin M . Calpain-dependent calpastatin cleavage regulates caspase-3 activation during apoptosis of Jurkat T cells induced by Entamoeba histolytica. Int J Parasitol. 2007; 37(11):1209-19. DOI: 10.1016/j.ijpara.2007.03.011. View

16.

Rosser B, Powers S, Gores G . Calpain activity increases in hepatocytes following addition of ATP. Demonstration by a novel fluorescent approach. J Biol Chem. 1993; 268(31):23593-600. View

17.

Goll D, Thompson V, Li H, Wei W, Cong J . The calpain system. Physiol Rev. 2003; 83(3):731-801. DOI: 10.1152/physrev.00029.2002. View

18.

Shao H, Chou J, Baty C, Burke N, Watkins S, Stolz D . Spatial localization of m-calpain to the plasma membrane by phosphoinositide biphosphate binding during epidermal growth factor receptor-mediated activation. Mol Cell Biol. 2006; 26(14):5481-96. PMC: 1592705. DOI: 10.1128/MCB.02243-05. View

19.

Goy A, Gilles F . Update on the proteasome inhibitor bortezomib in hematologic malignancies. Clin Lymphoma. 2004; 4(4):230-7. DOI: 10.3816/clm.2004.n.003. View

20.

Takano J, Tomioka M, Tsubuki S, Higuchi M, Iwata N, Itohara S . Calpain mediates excitotoxic DNA fragmentation via mitochondrial pathways in adult brains: evidence from calpastatin mutant mice. J Biol Chem. 2005; 280(16):16175-84. DOI: 10.1074/jbc.M414552200. View