Inhibitors of apoptotic proteins new targets for anticancer therapy

Inhibitors of Apoptotic Proteins: New Targets forAnticancer Therapy Mohammad Saleem1,2, Muhammad Imran Qadir1,*, Nadia Perveen1, Bashir Ahmad2, Uzma Saleem1,2, Tehseen Irshad3 and Bashir

Inhibitors of Apoptotic Proteins: New Targets for

Anticancer Therapy

Mohammad Saleem1,2, Muhammad Imran

Qadir1,*, Nadia Perveen1, Bashir Ahmad2, Uzma

Saleem1,2, Tehseen Irshad3 and Bashir Ahmad4

1

College of Pharmacy, GC University, Faisalabad, Pakistan

2

University College of Pharmacy, University of the Punjab,

Lahore, Pakistan

3

Foundation University Medical College, Islamabad,

Pakistan

4Faculty of Pharmacy, Bahauddin Zakariya University,

Multan, Pakistan

*Corresponding author: Muhammad Imran Qadir,

mrimranqadir@hotmail.com

Inhibitors of apoptotic proteins (IAPs) can play an

important role in inhibiting apoptosis by exerting their

negative action on caspases (apoptotic proteins)

There are eight proteins in this family: NAIP/BIRC1/

NLRB, cellular IAP1 (cIAP1)/human IAP2/BIRC2,

cellu-lar IAP2 (cIAP2)/human IAP1/BIRC3, X-linked IAP

(XIAP)/BIRC4, survivin/BIRC5, baculoviral IAP repeat

(BIR)-containing ubiquitin-conjugating enzyme/apollon/

BIRC6, livin/melanoma-IAP (ML-IAP)/BIRC7/KIAP, and

testis-specific IAP (Ts-IAP)/hILP-2/BIRC8 Deregulation

of these inhibitors of apoptotic proteins (IAPs) may

push cell toward cancer and neurodegenerative

disor-ders Inhibitors of apoptotic proteins (IAPs) may

pro-vide new target for anticancer therapy Drugs may be

developed that are inhibiting these IAPs to induce

apoptosis in cancerous cells

Key words: baculovirus IAP repeat (BIR), BIR-containing

(BIRC) proteins, inhibitors of apoptotic proteins (IAPs)

The problem of resistance and tolerance to the existing

drugs has created a decreased efficacy of these drugs in

use This problem has been tried to be overcome by

increasing the drug delivery to the target site by the use of

polymers (1,2) or through nanotechnology (3,4), synthesis

of new drugs, either by the use of proteomics (5), or

syn-thesis from lactic acid bacteria (6), or marine

micro-organ-isms (7) A large numbers of drugs are constantly being

invented for their possible pharmacological value

particu-larly for their antiinflammatory (8), hypotensive (9),

hepato-protective (10), hypoglycemic, amoebicidal, antifertility,

cytotoxic, antibiotic (11), spasmolytic (12), bronchodilator,

antioxidant (13), antidiarrheal (14), and anti-Parkinsonism

properties Similarly, as cancer is the major cause of death

in humans, new targets are being investigated for cytotoxic drug development

Inhibitors of apoptotic proteins (IAPs) were identified in ba-culovirus and have baba-culovirus IAP repeat (BIR) domain First IAP, OpIAP was recognized from a baculovirus strain

in 1993 by Miller and co-workers (15) Many IAP homologs inhibit apoptosis, but not all the IAPs establish cell death, but directly cause apoptosis regulation (16) All IAPs have one or more zinc-finger motifs called baculovirus IAP repeats (BIRs), the complete family specifically termed BIR-containing proteins (BIRPs or BIRC proteins) in spite

of IAPs Inhibitors of apoptotic proteins (IAPs) are given in Table 1

Structure of BIR Proteins

Inhibitors of apoptotic proteins (IAPs) inhibit caspase endogenously that are highly conserved throughout evolu-tion from Drosophila to vertebrates (17) There are eight proteins in this family, which are protein (NAIP/BIRC1/ NLRB), cellular IAP1 (cIAP1)/human IAP2/ BIRC2, cellular IAP2 (cIAP2)/human IAP1/BIRC3, X-linked IAP (XIAP)/ BIRC4, survivin/BIRC5, baculoviral IAP repeat (BIR)-con-taining ubiquitin-conjugating enzyme/apollon/BIRC6, livin/ melanoma-IAP (ML-IAP)/BIRC7/KIAP, and testis-specific IAP (Ts-IAP)/hILP-2/BIRC8 (Figure 1) There is at least one BIR domain that is required for their classification as IAPs There is 70- to 80-amino-acid-long motif in BIR domain that is related to their initial discovery in baculovirus, as indicated by the name (18) There are three BIR domains

at amino-terminal portion of mammalian IAPs, XIAP, cIAP1, and cIAP2 (19) Along with BIR motif, all IAP proteins except survivin have other functional domain, that is, the really interesting new gene (RING) and the caspase-acti-vating and recruitment domain (CARD) The RING domain has E3 ubiquitin ligase activity and regulates proteosomal degradation and ubiquitination of substrates Auto- or het-ero-ubiquitination of IAP proteins mediated with RING domain in regulatory loop or other substrates are degraded, for example, Smac and caspases Protein –pro-tein interactions are mediated by CARD domain that cause oligimerization with other proteins which have CARD and others which are involved in cell death regulation Along with mammalian IAP proteins, XIAP has most potent

Chem Biol Drug Des 2013; 82: 243–251

Review

antiapoptotic properties BIR domain mediates protein–

protein interactions but also has deep peptide-binding

groove that helps in specific binding BIR domains are

classified in to type 1 and type 2 domains, peptide-binding

groove is absent in type 1 BIR domain or only superficial

pocket is present N-terminal tetra-peptide called

IAP binding motifs (IBMs) are present in type 2 domain

IAPs such as XIAP, cIAP1, cIAP2, and Drosophila

mela-nogaster IAP1 (DIAP1) and DIAP2 are regulatory IAPs and

have two such types of BIR domains Caspases or IAP

antagonists cannot bind with these domains and interact

with these proteins differently As cIAPs which is type 1

binds with tumor necrosis factor receptor (TNFR)

associ-ated factor 1 (TRAF1) and TRAF2, while BIR1 of XIAPs

show interaction by transforming growth factor b (TgFb)

activated kinase (TAK1)-binding protein Binding of

N-ter-minal tetra-peptide called IAP-binding motif (IBMs) through

hydrophobic cleft There are two types of such BIR

domains in regulatory apoptosis IAPs such as XIAP, cIAP1,

cIAP2, and Drosophila melanogaster IAP1 (DIAP1) and

DIAP2 (20,21) BIR proteins, BIRC1,2,3,4,7,8 act on

casp-ases and BIRC5,6 and BIR-containing yeast and C

ele-gens act on cytokinin and mitotic spindle formation to

inhibit apoptosis (Figure 2)

BIRC1

Synonyms: Baculoviral IAP repeat-containing protein 1 (BIRC1), NAIP

The neuronal apoptosis inhibitory protein (NAIP), or BIRC1, was first discovered during spinal muscular atrophy due to positional cloning of contestant gene (22) Five to seven BIRC1 genes were identified depending on strains during amplification of BIRC1 locus in mouse strain Individual gene in BIRC1 has its own function, suggested in recent research Resistance to Legionella pneumophila infection

is due to BIRC1e, mapped to the Lgn1 locus (23) BIRC1a does not possess above function While BIRC1a knockout mice show increased neuronal death during their exposure

to kainic acid (24) BIRC1 show activity by binding with caspase 3, 7, and 9 in the presence of ATP, either it can inhibit enzyme activity or not is unclear (25,26) BIR domain present in BIRC1 binds to caspases, and oligo-merization domain is NACHT which helps in assembling signaling components Protein–protein interaction domain

is LRR domain which helps in pathogen sensing, but exact mechanism of apoptosis by BIRC1 is not clear (27–29), functions of BIRC1 are that they prevent apoptosis of motor neurons, tissue specificity is only in motor neurons but not in sensory neurons, localized in placenta and liver (30) but less significantly in spinal cord (Figure 3)

BIRC2

Synonyms: Baculoviral IAP repeat-containing protein 2 (BIRC2), C-IAP1, IAP homolog B (IAP-2, hIAP-2, hIAP2), Inhibitor of apoptosis protein 2 RING finger protein 48, TNFR2-TRAF signaling complex protein 2 API1, IAP2, MIHB, BIRC2 contains 3 BIR repeats, 1 CARD domain and 1 RING-type zinc finger motif

Figure 1: Inhibitor of apoptotic protein (IAP) family (BIR,

baculovirus IAP repeats; CARD, caspase-activating and

recruitment domain; RING, really interesting new gene).

Table 1: Inhibitors of apoptotic proteins (IAPs)

BIRC7 ML-IAP (livin), (K-IAP)

Figure 2: BIR proteins, BIRC1,2,3,4,7,8 act on caspases and BIRC5,6 and BIR-containing yeast and C elegens act on cytokinin and mitotic spindle formation to inhibit apoptosis.

BIRC2 has many functions along with caspase regulation

and apoptosis, helps in inflammatory as well as mitogen

kinase signaling, immunity, cell proliferation cell invasion,

and metastasis It regulates NF-kappa-B signaling by

canonical and non-canonical pathway by E3

ubiquitin–pro-tein ligase It acts as constitutive suppressor of

non-canon-ical NF-kappa-B signaling pathway and constructive

positive regulator of the canonical pathway E3 ubiquitin–

protein ligase activity is mediated by: RIPK1, RIPK2,

RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/

SMAC, AP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, and

MXD1/MAD1 proteins NEDD8 conjugation pathway,

neddylation and inactivation are mediated by an E3

ubiqu-itin–protein ligase by acting on caspases Innate immune

signaling is regulated by Toll-like receptors (TLRs), Nod-like

receptors (NLRs), and RIG-I-like receptors (RLRs), named

as pattern recognition receptors (PRRs) A large

multipro-tein complex ripoptosome that kill cancer cells in a

cas-pase-dependent and caspase-independent manner is

protected by BIRC2 Ripoptosome formation is suppressed

by ubiquitinating RIPK1 and CASP8 Transcriptional activity

of E2F1 can be stimulated BIRC2 has CARD domain,

which by inhibiting RING domain dimerization and E2

ubiquitin donor binding and activation helps in enzyme

reg-ulation Autoinhibition of the E3 ubiquitin–protein ligase is

mediated by CARD domain, which suppresses migration

and cell proliferation Stability of BIRC2/c-IAP1 is regulated

by USP19 by preventing its ubiquitination Apoptotic

sup-pressor activity is inhibited by interactions with DIABLO/

SMAC and with PRSS25 Also interact with TRAF2 via BIR

domains and E2F1, RIPK1, RIPK2, RIPK3, RIPK4, BIRC5/

survivin, and USP19 BIRC2 is found in nucleus and

cyto-plasm (31) Its nuclear localization is mediated by BIR

domain BIRC2/c-IAP1, CARD domain helps in protein

sta-bilization and of E3 ubiquitin–protein ligase activity inhibition

by preventing dimerization of RING domain and binding

and activation of E2 ubiquitin donor

BIRC3

Synonyms: Baculoviral IAP repeat–containing 3 (BIRC3),

apoptotic inhibitor 2, c-IAP2, cIAP2, hiap1, inhibitor of

apoptotic protein 1, MALT2, mammalian IAP homolog C (MIHC), RNF49, TNFR2-TRAF signaling complex protein Action of BIRC3 (NF-jB) by transcriptional factor dimmers (which have combination of p50, p52, c-Rel, p65/RelA, and RelB) in normal cells, these dimmers are in inactive form found in cytoplasm because of interactions of dimmers of NF-jB with IjB inhibitors NF-jB is activated through extracellular signals of membrane-bound receptors and modulator and adaptor proteins, and as a result of protea-some-mediated degradation of IjB induces nuclear translo-cation of NF-jB Degradation of IjB which is proteosomal is mediated by phosphorylation of IjB, by an IjB kinase (IKK) complex There are two main pathways of NF-jB: a canoni-cal pathway and a non-canonicanoni-cal pathway (Figure 4) There

is overlap in these pathways, at cytoplasmic effector pro-teins many signals at NF-jB pathways, which are being used by both pathways Canonical pathway is activated by p50–p65 complexes as a result of degradation of coupled

IjB, and non-canonical pathway is by dispension of dor-mant p100-RelB dimer to active p52-RelB due to degrada-tion of IjB C-terminal sequences of NF-jB2 p100 Proteosomal inhibitors can block NF-jB pathways, which

by inhibiting degradation of IjB proteins that interrupt

NF-jB signaling From different studies, it is revealed that MM cell lines have nuclear NF-jB activity and blockers of NF-jB signaling can inhibit growth of these NF-jB-positive MM cell lines (e.g., bortezomib, the proteasome inhibitor has much clinical efficacy for MM, which is largely due to anti-NF-jB signaling activity of bortezomib Function as apoptotic sup-pressor The BIR motifs region interacts with TNF receptor– associated factors 1 and 2 (TRAF1 and TRAF2) to form a heteromeric complex, which is then recruited to the tumor necrosis factor receptor 2 (TNFR2) Baculoviral IAP repeat-containing protein 3 has been shown to interact with TRAF1, TRAF2, RIPK1, Caspase-9 and UBE2D2 (21)

BIRC4

Synonyms: Baculoviral IAP repeat-containing protein 4 (BIRC4), XIAP-associated factor 1, BIRC4-binding protein (BIRC4BP), XIAPAF1, API3, IAP3

XIAP is the member of IAP family, which is most widely studied, found on X chromosome The only IAP, BIRC4 can inhibit caspases enzymatic activity BIRC4 causes inhibition of apoptosis by binding to TNF-alpha receptors-associated factor TRAF1 and TRAF2, and apoptosis is inhibited which is induced by menadione, a potent free radical inducer as well as interleukin-1-beta-converting enzyme It has BIR and RING finger domain It can be expressed in cell lines of mammals and can cause virally induced apoptosis blockade XIAP is a most potent apop-totic suppressor protein can inhibit cell death proteases by binding with at least two members of caspases, mostly caspase 3 and 7 (Figure 5) BIRC4 has many functions and act on caspases and inhibit apoptosis, also act as immunity and inflammatory signaling, mitogenic kinase sig-Figure 3: Different micro-organisms via caspases pathway show

inhibition of apoptosis.

naling, copper homeostasis, cell division, and metastasis.

It is located in nucleus and cytoplasm and found in adult

person’s carcinoma cell lines heart, placenta, lung, lymph

node, spleen, and ovary (32,33)

BIRC5

Synonyms: Baculoviral IAP repeat-containing protein 5

(BIRC5), apoptotic inhibitory survivin

BIRC5 like BIRC3 and 4 has many functions in cell division

and inhibition of apoptosis BIRC5 found in copious

amount in human fetal growth, but not in adult tissue, it

expressed in large quantity in lung, liver, heart, GIT (34)

colon, pancreas, prostate, and breast cancer and

trans-formed cell lines (35), but not in differentiated tissues apart

from thymus and placenta Also highly found in patients

with hematologic malignancies (36), lymphomas, acute

leukemias, and myelodysplastic syndromes, which leads

toward leukemia Survivin found in copious amount in

can-cer cells but absent in normal tissues (37) Tumor resis-tance to different stimuli increases by caspase-dependent pathway, but in caspase-independent pathway, it can inhi-bit apoptosis (38,39) During mitosis, survivin links with mitotic spindle microtubules, at start of mitosis, and found along with centromeres with caspase-3, and the cyclin-dependent-kinase inhibitor p21Waf1, so that they can form

an assembly Functions are defects in cell division and G2/M phase apoptosis BIRC5 has double role in cell divi-sion regulation and cell death control Survivin causes apoptosis by preventing microtubules integrity and in cen-tromere regulate cell cycle/cell death by assembly of supramolecular assembly (36) (Figure 6) BIRC5 is the pro-tein that shows antiapoptotic activity along with IAP having only one BIR domain

BIRC6

Synonyms: Baculoviral IAP repeat-containing protein 6 (BIRC6), Baculoviral IAP repeat-containing ubiquitin-conju-Figure 4: BIRC3 signaling pathway; mutations are shown in multiple myeloma by canonical and non-canonical pathway By this NF-jB, DNA binding and target gene expression are activated Arrows show activation whereas – sign show inhibition.

gating enzyme (BRUCE), Baculoviral IAP repeat-containing

6 (Apollon), FLJ13726, FLJ13786

BIRC6 is found in high quantity in brain, testis, lymphatic

cells, and secretory organs and also in many other

tis-sues It is found in high quantity in mouse embryos up

to E11, then transcript level falls found in the trans Golgi

network (TGN) membranes and the endosomal system It

is a member of IAP family BRUCE is a protein, at

amino-terminal having a single survivin-like baculoviral

IAP repeat (BIR) domain, and at carboxy-terminal, a

ubiquitin-conjugating enzyme domain Different studies

show that BRUCE is a dual regulator of cell proliferation

and cell death, as well as BRUCE in mammalian cells is

the only essential BIR-containing protein that involves in

cell growth and development BIRC6 is outer membrane

protein of the trans Golgi network acts as apoptosis

inhibitor by acting as inhibitor of apoptosis protein (IAP)

Caspase (3, 6, 7, 8, and 9) can be inhibited by BRUCE

(Figure 7) Additionally, it ubiquitylates cHtrA2 (a

proapop-totic serine protease) caspase-9, and DIABLO/Smac

(a competitor for caspase–IAP interactions) so, act on

them for proteasomal degradation For ubiquitylation

reactions, there is no need of ubiquitin E3 ligase which

makes BIRC6 a chimeric E2/E3 ubiquitin ligase BIRC6 is

overexpressed in many cell lines of brain and ovarian

cancer, overexpression of BIRC6 may correlate with

apoptotic reagent resistance BIRC6 also overexpressed

in bone marrow cells of myelodysplastic syndromes

Inhi-bition of apoptosis is mediated either by caspase binding

and or by inhibition IAP antagonist SMAC as well as caspase 9 ubiquitination so for proteosomal degradation proteins are targeted Apoptosis is mediated by BIRC6

by ubiquitination and proteasomal degradation (18) (Figure 7)

BIRC7

Synonyms: Baculoviral IAP repeat-containing protein 7 (BIRC7), melanoma inhibitor of apoptosis protein (ML-IAP) (43) BIRC7 functions as apoptotic regulator, shows action by proapoptotic and antiapoptotic activities and helps in apoptosis, cell division, cell cycle arrest Apoptosis is med-iated by caspase 3, 7, 9 and by its E3 ubiquitin–protein ligase activity, anticaspase activity is weak and by ubiquiti-nation DIABLO/SMAC targeting show antiapoptotic activ-ity By blocking of DIABLO/SMAC disrupt XIAP/BIRC4– caspase interactions show caspase inhibition (41) TNF or chemical agents such as adriamycin, etoposide, or stauro-sporine-induced apoptosis can be prevented by BRUCE Apoptosis suppression is mediated by MAPK8/JNK1, and also by MAPK9/JNK2, activation depends on TAB 1 and NR2C2/TAK1 Caspase 3 is inhibited by and proteolytic activation of procaspase 9 (Figure 8)

BIRC8

Synonyms: Baculoviral IAP repeat-containing 8 (BIRC8), ILP2, ILP-2, hILP2

Figure 5: Mechanism of action of BIRC4 through caspases pathway Healthy cells contain caspases in their uncleaved and inactive state (1) Mitochondria releases cytochrome C (Cyt C), which binds with ATP and Apaf-1 (2), apaf-1 binds with caspase 9 and activate it (3), activated caspase 9 causes cleavage and activation of caspase 3 (4), (7) BIRC4 present in the cytosol in sufficient amount binds with activated caspase 9 (5) and inhibits the activation of caspase 3 by caspase 9 As shown in this model, mitochondria releases Diablo\smac dimmers which make complex with BIRC4 and in this way caspase 9 becomes free and can activate caspase 3.

Figure 7: Mechanism of action

of BIRC6.

Figure 6: Mode of action of BIRC5/survivin through caspase pathway.

BIRC8 belonging to immunoglobin superfamily acts as a

genetic home, having many leukocyte Ig-like receptors,

killer cells, several ICAMs, the CEACAM and PSG family

and Fc receptors (FcRs) Its function is protection

against apoptosis caused by BAX subcellular structure

which binds to caspase 9, found in high quantity in

cytoplasm Tissue specificity is in testis (42), cancerous

tissue, and in normal tissues In number of viral and

eukaryotic proteins, RING-type zinc-finger motif is

pres-ent, which is made of cysteine-rich domain that binds

with two zinc atoms ILP2 has role in transformation and

progression, which protects cell by Bax-mediated

apop-tosis Apollon/livin/ILP2 possesses significant expression

in bone marrow cells of myelodysplastic syndromes

After transformation to overt leukemia, apoptosis

medi-ated by Fas and TNF have no protective effect after

overexpression of IPL (43)

Conclusion

Inhibitors of apoptotic proteins (IAPs) can play an

impor-tant role in inhibiting apoptosis by exerting their negative

action on caspases (apoptotic proteins) Deregulation of these inhibitors of apoptotic proteins (IAPs) may push cell toward cancer and neurodegenerative disorders It is con-cluded that inhibitors of apoptotic proteins (IAPs) may pro-vide new target for anticancer therapy Drugs may be developed that are inhibiting these IAPs to induce apopto-sis in cancerous cells

Declaration

Authors have no competing interests

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