Calpain as a therapeutic target in cancer

Figures & data

Figure 1. Structure of calpain-2 and domain diagram for CAPN1/2 and CAPNS1. (A) A three-dimensional structure of calpain-2 with color-coded domains, created with a structure from PDB 1KFU [13]. Grey molecular surfaces are inter-domain linkers flanking the CBSW domain in CAPN2, and the red surface is the N-terminal anchor helix of CAPN2. The GR domain of CAPNS1 is unstructured and thus not shown. (B) A domain diagram of calpain-1/2 showing the red N-terminal anchor helix, PC1 – protease core 1, PC2 – protease core 2, CBSW – calpain-type beta-sandwich, and PEF(L) – penta EF-hand in the catalytic large subunits, CAPN1/2; and the GR – glycine-rich, and PEF(S) – penta EF-hand in the regulatory small subunit, CAPNS1. Amino acids of the catalytic triad are shown with CAPN1 residue numbering. The double-ended red arrow indicates interactions of PEF(L) and PEF(S) mediating dimerization of CAPN1/2 with CAPNS1.

Figure 2. Binding sites for Ca²⁺, CAST and small molecule inhibitors of calpain-2. White spheres represent Ca²⁺ ions. The different domains in CAPN2 and CAPNS1 are colored as in Figure 1. Individual peptide A, B and C motifs of calpastatin (CAST) are shown in crimson, binding to the CAPN2 PEF(L) domain, across the active site, and the CAPNS1 PEF(S) domain, respectively. Molecular structures of inhibitors are shown at the binding positions for two proposed modes of small-molecule inhibition of calpain; active site directed (E64) and allosteric site through binding to the CAPNS1 PEF(S) domain (PD150606). Highlighted residues C105, H262 and N286 comprise the catalytic triad of calpain-2. This 3D representation is based on PDB structures 1KFX [13], 3DF0 [24], 1TLO [25], and 1NX3 [26].

Table 1. Biologically relevant calpain substrates validated in vivo.

Substrate	Cleaved by	Type of Cancer*	Molecular/physiological context	References
Apoptosis Inducing Factor (AIF)	Calpain-1	Human non-small cell lung cancer	In U1810 cells, mitochondrial AIF is cleaved into a 57 kDa fragment that is subsequently released into the cytosol to promote apoptosis.	[101]
Androgen Receptor (AR)	Calpain-1	Prostate	In LNCaP cells, cleavage of AR produces ~80 kDa truncated fragment, contributing to prostate cancer cell survival.	[36]
Bax	Calpain-1/2	Breast, Leukemia	In Jurkat T and MCF-7 cells, Bax is cleaved into an 18 kDa fragment which promotes the release if cytochrome C and downstream activation of caspases.	[94]
Beclin-1	Calpain-1/2	Colorectal	In Ras mutant intestinal epithelial cells, calpain mediated degradation of beclin-1 promotes anchorage-independent growth.	[37]
β-catenin	Calpain-2	Breast, Prostate	N-terminal cleavage of β-catenin produces a 75kDa fragment that accumulates in the nucleus, promoting transcription of the Wnt signalling pathway.	[126]
BID	Calpain-2	Melanoma	Calpain cleaves BID into a 14kDa fragment in cisplatin-treated cells, resulting in an increase in cytochrome C release from the mitochondria.	[96]
Caspases	Calpain-1/2	Breast, Cervical, Neuroblastoma	Calpain-mediated cleavage directly activates caspases-3, 7, 10 and 12, and inhibits caspase-9.	[38,39]
CDK5	Calpain-2	Multiple	Calpain cleaves CDK5 cofactors p35 and p39 into p25 or p29 respectively, producing holoenzymes with longer half-lives, greater solubility and altered substrate specificity. Note that CDK5/p25 is also associated with neurodegenerative diseases.	[40,100]
Cortactin	Calpain-2	Breast	Cleaved between the actin binding repeats and the α-helical domain to promote invadopodium disassembly and cell migration.	[41,86,122,123]
CRMP-4	Calpain-2	Prostate	Cleaved into an N-terminal fragment, promoting migration and invasion via nuclear translocation and activation of DNA methyltransferase.	[65]
Cyclin E	Calpain-2	Breast	Cleaved into low molecular weight fragments that contribute to enhanced CDK activity, angiogenesis and metastasis.	[42,115]
E-Cadherin	Calpain-1/2	Breast, Prostate	Calpain cleaves within the cytoplasmic domain, preventing association of E-cadherin with β-catenin, γ-catenin and p120.	[125]
EGFR	Calpain-1	Breast	Calpain cleaves within cytoplasmic domain to downregulate kinase activity.	[111]
Ezrin	Calpain-1	Breast	First reported as a calpain substrate in gastric parietal cells, ezrin has also been implicated in focal adhesion dynamics and invadopodia turnover in MDA-MB-231 cells. Furthermore, ezrin regulates calpain-1 localization to promote cleavage of cortactin, FAK and talin.	[43,86]
FAK	Calpain-2	Breast, Colon	Cleavage to promotes focal adhesion turnover and cancer cell migration.	[86,87,120]
FLNA	Calpain-1/2	Melanoma, Prostate, Mouse Fibrosarcoma	Cleavage promotes increased nuclear localization of HIF1-α to promote tumor growth and angiogenesis.	[131,132]
HER2	Calpain-1	Breast	HER2 is cleaved in juxta- membrane region, cleavage products result in feedback inhibition of HER2, regulating trastuzumab sensitivity.	[111]
c-MYC	Calpain-1/2	Lymphoma, Prostate, Colon, Neuroblastoma	Cleaved into ‘myc-nick,’ promoting microtubule stabilization, autophagy, and drug resistance.	[104]
P53	Calpain-2	Breast, Cervical, Colon	Calpain cleavage facilitates p53 degradation and attenuation of apoptosis.	[44]
PP2A	Calpain-1/2	Breast	Calpain cleaves the B56 subunit of PP2A, preventing its association and subsequent deactivation of AKT.	[108]
PTP1B	Calpain-2	Breast	Cleavage releases PTP1B from the ER, thereby increasing its phosphatase activity and promoting invadopodium formation via Src.	[123]
Rb	Calpain-1	Cervical	Calpain cleavage results in degradation thereby alleviating repression of pro-tumorigenic E2F transcription factors.	[45,46]
RhoA	Calpain-1	Breast	Calpain mediated cleavage activates RhoA and inhibits cell spreading, promoting migration.	[47,124]
Spectrin	Calpain-1/2	Gastric, Lung, Leukemia	Well-established calpain substrate often used as an indicator of calpain activity. Cytoskeletal protein with roles in cell motility, apoptosis, platelet activation and long term potentiation.	[48,138]
Talin	Calpain-1/2	Multiple cancers	Calpain cleavage mediates cell adhesion and cytoskeletal remodelling to promote cancer cell migration.	[119]
Vinculin	Calpain-1/2	Multiple cancers	Cleavage promotes MT1-MMP membrane translocation and subsequent endothelial sprouting, supporting tumor angiogenesis.	[49]
C-fos/C-jun	Calpain-1/2	Mammalian cells (MEFs, NIH3T3)	PEST-containing transcription factors degraded by calpain, thereby regulating gene expression and apoptosis.	[35,99]
Dysferlin	Calpain-1/2	Muscular dystrophy	Cleaved into mini-dysferlin that promotes cell membrane repair.	[141,153]
NCS-1	Calpain-1	Chemotherapy induced peripheral neuropathy	Degradation results in loss of intracellular calcium signalling and irreversible damage to peripheral nerve fibers.	[83]
Src	Calpain-1	IschemicStroke, Neurodegenerative Diseases	Cleaved into a 52kDa truncated protein that facilitates neuronal cell death via AKT inactivation.	[50]

* Note: Type of cancer refers to the subtype(s) explored within the references provided. Many substrates/cleavage products have important biological functions in multiple cancer subtypes, as well as normal cell physiology. The last four entries are calpain substrates with established physiological relevance in non-cancer contexts.

Figure 3. Calpain substrates in cell survival and apoptosis. Calpains become activated by increases in intracellular Ca²⁺ concentration, through Ca²⁺ influx or release from intracellular stores. Calpains are implicated in many key signalling pathways associated with cell death and survival including the PI3K-AKT [107,108], ERK [113], p53 [102], MYC [104,105], caspase [38,39] and AIF pathways [101]. Created with BioRender.com.

Figure 4. A schematic representation of calpain substrates in cell motility. Calpain cleaves PTP1B to facilitate its relocalization from the ER to the cytosol. There, PTP1B de-represses Src which subsequently activates cortactin and promotes actin branching – a key event in the formation of invadopodia structures. Calpain-1 cleaves Src kinase [50], and calpain-2 cleaves paxillin (PXN), focal adhesion kinase (FAK) and talin (TLN1) [127]. Vinculin (VCL) is a calpain substrate, but isoform specificity is unknown [128]. Colocalization of PXN, FAK, VCL and TLN1 at FAs and their structural organization are demonstrated [129]. Src is also localized at FAs [130].Created with BioRender.com

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