Table 4 Function of CDK2 based on cell line studies

Acute myeloid leukemia

CDK2 and CPS2

NB4, U937 and

HL60

PROTACs: ↑ CDK2 degradation and ↑ differentiation of AML cell lines

CPS2 was found to induce differentiation by CDK2 degradation

[92]

CDK2-PRDX2 axis, KLHL6

Leu-1-19, NB4, and U937, U2OS, COS-7, HeLa

∆ CDK1: ↑ granulocytic differentiation in AML cell lines and reactivation of differentiation pathway translation

KLHL6 was found to mediate degradation of CDK2

CDK2 blocks differentiation in AML cell lines by maintaining the activity of PRDX2

[93]

CDK2-SKP2 axis and C/EBPα

HL-60, THP-1 and U937

CDK2 enhanced stabilization of SKP2 via phosphorylating it which in turn induced C/EBPα degradation

[94]

CDK2 and C/EBPα

K562, THP‐1, U937, HEK293T and MCF‐7

CDK2 mediated C/EBPα ubiquitin proteasome degradation leading to destabilization of it which in turn leading to differentiation arrest in AML

[100]

TBK1 and AKT-CDK2 pathway

Kasumi-1, HL-60 and THP-1

Down-regulation of TBK1 induced daunorubicin sensitivity via the AKT-CDK2 axis

GSK8612, a TBK1 inhibitor, reduced TBK1-AKT-CDK2 expression

[95]

HDAC3-AKT-P21-CDK2 signaling pathway

K562, K562/A02, HL60, HL60/ADR, THP-1, THP-1/ADR, HEK293T,

Chidamide could inhibit HDAC3-AKT-P21-CDK2 signaling so induces sensitivity of anthracycline

∆ HDAC3: ↓

proliferation, ↑ apoptosis, cell cycle arrest at G0/G1 phase, and ↓ AKT, P21, and CDK2

[101]

CDK2

U937, NB4, HL60,

and 293FT

∆ CDK2: ↓ proliferation, ↑ G0 /G 1 phase arrest and sensitivity of AML cells to ATRA-induced cell differentiation

[102]

CDK2

HL-60

Roscovitine, an inhibitor of CDK2: ↑ ATRA-induced leukemia cell differentiation

[103]

CDK2, CyclinD3,Hsp90,EGFR, P27, Caspase 7, and TNF

HL-60

Combination of HAA2020 and dinaciclib: ↓ proliferation, survival and ↑ apoptosis via reducing the levels of CDK2, CyclinD3, Hsp90, EGFR, and increasing the levels of P27, Caspase 7, and TNF

[104]

Bladder cancer

miR340/CDK2 axis

5637 cells

Propofol treatment: ↓ proliferation and ↑ apoptosis via regulating miR340/CDK2 axis

[96]

Cdk2, Rad9 and Bak.Bcl-xl complex

MGC-803, HepG2, NCI-H460, A549, T24 and SKOV-3

Palbociclib: ↑ apoptosis via Cdk2-induced Rad9-mediated reorganization of the Bak.Bcl-xl complex

Palbociclib was found to play its role via Cdk2 activation

[97]

miR-3619, CDK2, β-catenin and p21

5637, EJ, T24, J82 and SV-HUC-1

↑↑ miR-3619: ↓ proliferation, migration, invasion, EMT process and ↑ apoptosis via downregulating β-catenin and CDK2

[105]

CDK2 and its 5 substrates

T24, J82, and RT4 BC

CDK2 and its 5 substrates was found to be involved in cisplatin chemotherapy

[106]

MTHFD2, CDK2, and E2F1

HEK‐293T, UMUC3 and T24

MTHFD2 was found to increase CDK2 and induce bladder cancer cell growth by modulating the cell cycle, thus affecting E2F1 activation

[107]

Breast cancer

C-MYC, CDK2, CDK4/6, and cyclin E

MCF7, MCF7-PR, T47D-PR, T47D

∆ CDK2 and CDK4/6: ↓ Palbociclib resistance through inducing senescence

[98]

CDK2/EZH2 axis and ESR1

T47D, MDA-MB-231 TNBC cells, BT549, Hs578T, SUM-149, and BT 549

Phosphorylation of EZH2 by CDK2 induces tumorigenesis

ESR1 gene encoding ERα was found to be a target of CDK2/EZH2 axis

∆ CDK2 or EZH2: ↑ re-expression of ERα and ↑ converting TNBC to luminal ERα-positive

[99]

TROJAN, CDK4/6, NKRF, RELA, and CDK2

MCF7, T47D and HEK293T

TROJAN induces ER + breast cancer proliferation and CDK4/6 inhibitor resistance via binding to NKRF and suppressing its interaction with RELA, so increases the expression of CDK2

[108]

BRCA1, cyclin E1, CDK2, PARP

HCC1937, MDA-MB-468, MDA-MB-436, MDA-MB-231, SkBr3, and BT-20

∆ CDK2: ↑ DNA damage to synergize with PARP inhibition

[109]

ACTL6A/MYC/CDK2 axis

293FT, MCF-7, MDA-MB-468 and MDA-MB-231, ZR-75-1, BT-474, and BT-549, SKBR-3, and SUM159PT

↑↑ ACTL6A: ↑ proliferation via recruitment of MYC and KAT5 on CDK2 promoter, so increasing its levels

K03861 (CDK2 inhibitor) and paclitaxel: ↓ growth

[110]

Breast cancer

CDK2 and CDK4

MCF-10A,

MDA-MB-231 and Hs578T

4-AAQB treatment: ↑ cell cycle arrest, DNA damage, and apoptosis via suppressing CDK2 and CDK4

[111]

CDK2

MCF-7

3-hydrazonoindolin-2-one scaffold (HI 5): ↓ proliferation and ↑ G2/M phase arrest via suppressing CDK2

[112]

MAFG-AS1/ miR-339-5p/CDK2 axis and ER pathway

MCF-7

↑↑ MAFG-AS1: ↑ ER + breast cancer proliferation by sponging miR-339-5p, and in turn increasing CDK2

[113]

RHBDD1, Akt and CDK2

MDA-MB-231 and MCF7

∆ RHBDD1: ↓ proliferation, migration, invasion, and ↑ apoptosis by suppressing Akt activation and decreasing CDK2 protein level via proteasome pathway

[114]

p27 Y88, cdk4 and cdk2

MCF7

ALT blocks p27 Y88 phosphorylation and suppresses activity of cdk4 and cdk2

[115]

Lnc712/HSP90/Cdc37 complex and CDK2

MCF-10A, MDA-MB-231 and MCF-7 and MCF-7/ADM

Lnc712/HSP90/Cdc37 complex increased proliferation via CDK2 activation

[116]

p27 pY88, cdk4 and cdk2

MCF7, MB231, T47D HCC1954

ALT + PD combination: ↑ cellular senescence and cell cycle arrest via inhibiting both cdk4 and cdk2

(ALT was found to prevent p27 pY88 and inhibit both cdk4 and cdk2)

[117]

CDK2

MDA-MB-468

Benzamide derivative compound 25: ↓

proliferation, ↑ apoptosis, cell cycle arrest via inhibiting CDK2

[118]

CDK2

MCF-7

thiazolone and the fused thiazolthione derivatives: ↑ G1/G2-M phase arrest and apoptosis via inhibiting CDK2

[119]

CDK2, AKT

SKBr3 and T47D

Higenamine: ↑ antitumor effects of cucurbitacin B via suppressing the interaction of AKT and CDK2

[120]

CDK2

MDA-MB-231, MDA-MB-468

CRIF1-CDK2 interface inhibitors, F1142-3225 and F0922-0913, and Paclitaxel combination: ↓

proliferation, ↑ apoptosis

[121]

CDK2, pS294, ER

MCF7

CDK2 was found to mediate pS294 formation

Selective CDK2 inhibitors suppress pS294 and ER-dependent gene expression

ESR1 mutations increased ligand-independent and tamoxifen-resistant tumor growth

CDK2-selective inhibitors like Dinaciclib could prevent pS294 formation and suppress ER-dependent gene expression

[122]

CDK2, PPM1H, p27

MDA-MB-231

↑↑ PPM1H: ↑ paclitaxel sensitivity via dephosphorylation of p27

CDK2 was found to induce resistance to paclitaxel

[123]

Breast cancer

CDK2, CDK9

MDA-MB-23, MDA-MB-436, and Hs578T

CDK2/9 inhibitors, CYC065 and eribulin combination: ↓ proliferation, ↑ apoptosis

[124]

CDK2, cyclin D1, cyclin E

MCF-7

HSYB, an isomer of HSYA with antioxidative effects: ↓ proliferation and ↑ cell cycle arrest at the S phase via downregulating cyclin D1, cyclin E, and CDK2

[125]

CDK2

MCF-7

Arylazopyrazole, 8b: ↑ apoptosis and cell cycle arrest

The binding mode of 8b was was found to bind to the active site of CDK2 via three hydrogen

bonds

[126]

CDK2, p21

DA-MB-231 and MCF-

7, and HAECs

pyrvinium pamoate and tigecycline combination: ↓ proliferation, levels of CDK2 but ↑ cell cycle arrest at G1/s phase, and levels of p21 increased

[127]

Cervical cancer

hsa_circ_0000520/ miR-1296/CDK2 axis

SiHa, HT-3, Hela, SW756 and ME-180

∆ hsa_circ_0000520: ↓ proliferation and ↑ apoptosis via up-regulating CDK2

[128]

circ_0084927/miR-1179/CDK2 axis

HeLa, CaSki, SW756 and C-33A, and HcerEpic

∆ circ_0084927: ↓ proliferation and ↑ cell cycle arrest via regulating miR-1179/CDK2 axis

[129]

circZFR, SSBP1, CDK2/cyclin E1 complexes, p-Rb, and E2F1

HeLa and SiHa

∆ circZFR: ↓ proliferation, migration, invasion, and tumor growth

circZFR interacted with SSBP1, so promotied the assembly of CDK2/cyclin E1 complexes, and induced p-Rb phosphorylation

[130]

CDK2/E1complex

HeLa

Thiazol-hydrazono-coumarin hybrids, compound 8a, led to cell cycle attesst at G0/G1 phase and apoptosis by targeting CDK2/E1complex

[131]

Cholangiocarcinoma

CDK2/5/9

HuCCT1 and KMCH

Dinaciclib treatment: ↓ proliferation and ↑ apoptosis via suppressing CDK2/5/9

[132]

Colorectal cancer

NPTX1, cyclin A2, CDK2, and Rb-E2F signaling

SW480 and HCT116

↑↑ NPTX1: ↓ proliferation via downregulating cyclin A2 and CDK2, thereby regulating the Rb-E2F signaling

[133]

CDK2

HCT116

Topane-based compounds (Compounds 26 and 33) could be anticancer agents via inhibiting CDK2 inhibitors

[134]

MEX3A and CDK2

HIEC-6, SW480, HCT116 and HT29

∆ MEX3A: ↓ viability, proliferation and invasion and ↑ apoptosis via downregulating CDK2

[135]

CDK2/9

CRC057, CRC119, CRC16-159, CRC240, CRC247, and CRC401

Dual CDK2/9 inhibition: ↑ G2-M arrest and anaphase catastrophe

[136]

SLCO4A1-AS1, Cdk2, c-Myc

HT29, LoVo, HCT116, SW620, and SW480, and NCM460

SLCO4A1-AS1 promotes colorectal tumorigenicity by increasing Cdk2 levels and activating the c-Myc signaling

[137]

Gastric cancer

CDK2/SIRT5 axis

MGC‐803 and SCG‐7901

∆ CDK2: ↓ aerobic glycolytic capacity and ↑ levels of the SIRT5 tumor suppressor

[138]

LINC01021, CDK2, CDX2, KISS1

SGC-7901, NCI-N87, BGC-823, and GES1

∆ LINC01021: ↓ migration, invasion, and angiogenesis via inducing the binding between CDX2 and KISS1, and suppressing that between CDK2 and CDX2

[139]

PCBP2 and CDK2

HGC‐27 and MKN‐45

∆ PCBP2: ↓ Colony formation and viability

[140]

Glioblastoma

Cyclin-CDK2 Pathway

GBM8901 and U87

Water extract of G. lucidum: ↓ proliferation, migration, and ↑ mitochondria-mediated apoptosis and cell cycle arrest at S phase via the cyclin-CDK2 pathway

[141]

Glioma

LINC00958/ miR-203/CDK2 axis

SHG44, U87, U251, A172, and NHAs

∆ LINC00958: ↓ proliferation, invasion, and ↑ cycle arrest at G0/G1 phase

LINC00958 promotes gliomagenesis via miR-203/CDK2 axis

[142]

HSP90AA1-IT1/miR-885-5p/CDK2 axis

NHA, U87MG and U251

∆ HSP90AA1-IT1: ↓ viability, proliferation, EMT, invasion and migration and ↑ apoptosis

HSP90AA1-IT1 plays its role via regulating miR-885-5p/CDK2 axis

[143]

Hepatocellular carcinoma

CDK2/4/6, cyclin D/E, Rb

QGY7703 and Huh7

vanoxerine dihydrochloride treatment: ↑ G1-arrest, apoptosis, and ↓ expressions of CDK2/4/6

[144]

HNRNPU, CDK2

HEK293T, HepG2 and Huh7, MHCC97H

↑↑ HNRNPU: ↑ proliferation via enhancing the transcription of CDK2

[145]

EGFR-CDK2 signaling

human hepatoma cells

It was found that Cinobufagin could play its antitumor effects by suppressing EGFR-CDK2 signaling

[146]

MAPRE1 and CDK2

Huh7

MAPRE1 was found to bind with CDK2 and promote HCC progression

[147]

OLA1, P21, and CDK2

Hep3b, Hep G2, LM3, MHCC-97H and HEK293T

∆ OLA1: ↓ proliferation, migration, invasion, and G0/G1 ↑ phase arrest and apoptosis

OLA1 promotes tumorigenicity via binding with P21 and up-regulating CDK2 expression

[148]

TPT1-AS1, CDK2

SNU-398 and SU.86.86

↑↑ TPT1-AS1: ↓ proliferation via down-regulating CDK2

[149]

LINC00630, E2F1, CDK2

Bel-7402, SK-Hep1, MHCC-97H, HepG2, and L02

↑↑ LINC00630: ↑ proliferation and ↓ apoptosis via enhancing the binding of E2F1 to the CDK2 promoter region, so promoting CDK2 transcription

[150]

Leukemia

CDK2, p21, p27, p53 and FasR

THP-1 and NHMs

Combination of DOX and PGZ: ↓ cell growth and ↑ G2/M arrest via reducing the levels of CDK2 and increasing the levels of p21, p27, p53 and FasR

[151]

CDK2

MOLT-4 and HL-60

Pyrazolo[1,5-a]pyrimidines (5 h and 5i) showed the best CDK2 inhibitory activity

[152]

Liver cancer

miR-155, H3F3A CDK2, P21WAF1/CIP1

Hep3B

miR-155 inhibits H3F3A, so promotes the phosphorylation modification of CDK2, thus, miR-155 suppresses the transcription and translation of P21WAF1/CIP1

[153]

Lung cancer

miR-597/CDK2 axis

H1299 and PC-9

↑↑ miR-597: ↓ proliferation via targeting CDK2

[154]

p21/CDK2/Rb signaling pathway

NSCLC cells

PPI was found to disturb CDK2 function through increasing p21, thus PPI could suppress Rb via the p21/CDK2/Rb signaling pathway

PPI and Palb combination: ↑ anti-cancer ability on NSCLC

[155]

CCNA2-CDK2 complex and AURKA/PLK1 pathway

A549 and NCI-H1975, BEAS-2B, and LLC

Tanshinone IIA: ↓ cancer progression via regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway

[156]

CDK2/9

ED1, LKR13, 393P, H522, H1703, A549, Hop62, and H2122

CDK2/9 inhibitor, CCT68127: ↓ growth, and ↑ G1 or G2/M arrest

[157]

STAT3/ VEGF/ CDK2 axis

A549 and H460

PROS plays its antiangiogenic role via inhibiting STAT3/ VEGF/ CDK2 axis

[158]

AKT, CDK2

A549, A427, NCI-H23, NCI-H358, NCI-H1975, and NCI-H1650

A-674563, a putative AKT1 inhibitor that altered cell cycle progression and off-target CDK2 inhibition, suppresses tumor growth more effectively than the pan-AKT inhibitor, MK-2206

[159]

Medulloblastoma

CDK2 and MYC

MYCN-driven mouse MB cells and hindbrain NSCs, Sai2, AF22, MB002, CHLA25, Kelly

BET bromodomain inhibition and CDK2 inhibition: ↑ cell cycle arrest and apoptosis via suppressing MYC expression and MYC stabilization

[160]

Melanoma

CDK2

MDA-MB-435 and SNB-75, WI-38

Quinazolinone-based derivatives (compounds 5c and 8a) had significant growth inhibition against melanoma via inhibiting CDK2

[161]

Melanoma and non-melanoma skin cancers

CDK2

A375 and SK-Mel-28, A431 and UWBCC1

Flavonol-based derivatives of fisetin, compounds F20, F9 and F17, were found as c-Kit, CDK2 and mTOR inhibitors

[162]

Neuroblastoma

CDK2, MDM2, CDK1, PSMD14 and TSPO (p53 signaling pathway)

IMR32

Down-regulation of CDK2 showed that MDM2, CDK1, PSMD14 and TSPO could be key target genes of CDK2

[163]

Ovarian cancer

CDK2, EZH2, ESR1

SKOV3, OVCA433, CAOV3, DOV13, A2780, OVCA420

∆ CDK2: ↓ phosphorylation of EZH2 at T416, thus increased the expression of its downstream target ERα gene (ESR1)

[164]

PLAC2 and CDK2

UWB1.289

↑↑ PLAC2: ↑ proliferation via regulating CDK2

[165]

Cul4B, miR-372, CDK2 and CyclinD1

Hey, PEA-1, SKOV-3 and OVCAR3

↑↑ Cul4B: ↑ proliferation by sponging miR-372 and regulating CDK2 and CyclinD1

[166]

Prostate cancer

CDK2 and PI3K/Akt pathway

PC-3, DU-145 and 22RV1

∆ CDK2: ↓ invasion and metastasis via inactivating PI3K/Akt pathway

[167]

Renal cell carcinoma

SKP2-p21/p27-CDK2 axis

786-O, 769-P, OSRC-2, Caki-1, and HK-2

Nobiletin: ↓ proliferation and ↑ G1 cell cycle arrest and cell apoptosis via decreasing SKP2 by reducing its transcriptional level, thus increasing p27 and p21 levels, which inhibited CDK2

[168]

WTAP and CDK2

HK2, Caki-1, Caki-2, ACHN, 769P, 786-O

∆ WTAP: ↓ proliferation

WTAP plays its oncogenic role via binding to CDK2 transcript and increasing its transcript stability

[68]

TSG101, c-myc, cyclin E1 and CDK2

A498 and 786-O

∆ TSG101: ↓ proliferation, colony formation and ↑ G0/G1 arrest via down-regulating c-myc, cyclin E1 and CDK2

[169]

Soft tissue leiomyosarcoma

PLA2G10, cyclin E1 and CDK2

SK-LMS-1

PLA2G10 promotes tumorigenicity via enhancing expression of cyclin E1 and CDK2

[170]

T-cell acute lymphoblastic leukemia

SIRT1, p27, CDK2, SKP2

CCRF-CEM, MOLT4, KG-1, THP-1. MV4–11, K562, U937 and 293T

SIRT1 was found to by deacetylate CDK2 and induce the interaction between p27 and SKP2 leading to phosphorylation of p27, thus the degradation of p27

Notch1/Myc axis increased SIRT1 protein level

[171]