Table 5 Role of PI3K/AKT pathway in oral squamous cell carcinoma

Male Balb/c nude mice

CAL-27, SCC-9

Lycopene

0–2 µM

Bax, Bcl-2,

E-cadherin,

N-cadherin

PI3K/AKT,

mTOR,

EMT

Lycopene by suppressing the EMT pathway and activating the PI3K/AKT/mTOR pathway could induce apoptosis and inhibit invasion, cell proliferation, and migration of OSCC cells

[69]

–

KB, K562, MCF-7

Thymoquinone (TQ)

0–2 µM

–

PI3K/AKT

TQ through suppression of the PI3K/AKT pathway could suppress invasion, proliferation, migration and induce apoptosis in OSCC cells

[70]

TSCC (n = 72 patients)

SCC4, SCC15, SCC25, Hs 680

–

–

LncRNA MALAT1, MMP-9

PI3K/AKT

Suppression of lncRNA MALAT1 could inhibit invasion, migration, and proliferation of TSCC cells via suppressing the PI3K/AKT pathway and down-regulating MMP-9

[72]

52 OSCC tissues with the corresponding non-tumor tissues

CGHNK2, SCC25, HSC3

–

–

FBXW7,

miR-27a, Vimentin,

N-cadherin,

E-cadherin

PI3K/AKT

Up-regulation of FBXW7 and downregulation of miR-27a via the PI3K/AKT pathway can suppress the proliferation and cell growth of OSCC

[74]

OSCC (n = 80), adjacent non-tumor tissues (n = 7)

HUVEC, CAL27

–

–

miR-210-3p, EFNA3

PI3K/AKT

miR-210-3p by increasing the phosphorylation rate of AKT could promote OSCC cells angiogenesis, migration, and proliferation

[75]

Datasets

HO1-N-1,

SCC-9,

HNOEC

–

–

ITGA5,

ERK

PI3K/AKT

ITGA5 via the PI3K/AKT pathway could play an oncogenic role and promote invasion, proliferation, and migration of OSCC cells

[76]

57 pairs of OSCC and adjacent non-tumor tissues, female

BALB/c nude mice

Tca-8113,

SCC-15,

HOK

CircCDR1,

HIF-1α, p62, LC3I/II, ATG5, Bax, Bcl-2,

Caspase-3

AKT,

ERK1/2,

mTOR

CircCDR1 via the AKT/ERK/mTOR pathway could improve the viability of OSCC cells by promoting autophagy

[73]

BALB/c nude mice

SCC4, CAL-27

Licochalcone A

0–100 μM

PCNA,

MMP-2/9

PI3K/AKT

Licochalcone A could suppress OSCC cells migration, invasion, and proliferation via modulation of the PI3K/AKT pathway

[71]

98 paraffin embedded OSCC samples

HSC3, OSCC3, SCC4, SCC7, Cal27, HaCaT

–

–

SPARC, PDGFB,

PDGFRβ

PI3K/AKT

SPARC via the PI3K/AKT/PDGFB/PDGFRβ axis could promote metastasis and proliferation of OSCC cells

[77]

male Syrian hamsters

SCC131,

SCC4

Astaxanthin (AXT), wortmannin, Bay-11,

S31-201

0–1200 μM,

0–200 nM,

0–10 μM,

0–120 μM

NF-kΒ, Bcl-2, Bax, Cyclin-D1, p21, MMP-2/9,

Caspase-3/9,

HIF-1α, VEGF, VEGFR2

PI3K, STAT3

AXT in combination with wortmannin, Bay-11 or S3I-201 via the PI3K/NF-kΒ/STAT3 axis could suppress apoptosis evasion, invasion, proliferation, and angiogenesis of OSCC cells

[78]

124 pairs of paraffin-embedded OSCC and adjacent tissues, female BALB/c mice

SCC15,

SCC25

–

–

TGF-β, SOX2, BMI1, ERK1/2, ABCG2, CD44, IVL

AKT/FOXO3a

TGF-β via AKT/FOXO3a axis could induce stemness in OSCC

[76]

62 pairs of OSCC and adjacent non-tumor tissues, female BALB/c nude mice

SCC25,

Cal27

–

–

B7-H3, PFKFB3, Glut1

PI3K/AKT,

mTOR

Protein B7-H3 via the PI3K/AKT/mTOR pathway could increase tumor glucose uptake, aerobic glycolysis and metastasis in OSCC

[73]

20 pairs of OSCC and adjacent non-tumor tissues, athymic nude mice

SCC9 SCC15, SCC25, CAL27, hTERT-OME

Tanshinone IIA

0–5 μM

HK2/1, VDAC1, Bax, GSK-3β, Caspase-3, PARP

AKT/c-Myc

Tanshinone IIA via the AKT/c-Myc pathway could inhibit OSCC by reducing of glycolysis

[74]

TSCC (n = 40)

Cal 27,

SCC9

–

–

miR-21-5p, Bax, Bcl-2, PDCD4, FOXO1

PI3K/AKT

Downregulation of miR-21-5p by targeting PDCD4 that knockdown the PI3K/AKT/FOXO1 pathway could inhibit the invasion and proliferation of TSCC

[79]

BALB/c nu/nu nude mice

HOMEC, TSCCA, SCC15,

CAL27

–

–

Per2, LC3B, p62, Beclin-1

PI3K/AKT,

mTOR

Per2 via the PI3K/AKT/mTOR pathway can inhibit OSCC progression by activating autophagy

[80]

50 sample of OSCC and 10 of adjacent non-tumor tissues, female athymic nude mice

CAL27, HSC4, SCC15, 293 T

–

–

USP13, GLUT1,

HK2

PTEN/AKT

USP13 via regulating PTEN/AKT pathway act as a tumor suppressor

[81]

Male Balb/c‐nude mice

TSCCa,

Tca‐8113

CCN5, Bax,

Cyclin-D1/E, CDK2, Bcl-2, Procaspase-3/9

PI3K/AKT

CCN5 via the PI3K/AKT pathway can suppress proliferation and promote apoptosis of OSCC

[82]

116 pairs of OSCC and adjacent non-tumor tissues

SCC-25,

HOK

–

–

PAR-2

PI3K/AKT,

mTOR

PAR-2 via the PI3K/AKT pathway could enhance invasion, migration, and proliferation of OSCC cells

[83]

BALB/c nude mice

SCC 4, HSC3, CAL27, HN6, HOK

–

–

TROP2, PTEN, PDK1

PI3K/AKT

TROP2 via PI3K/AKT could promote cell growth, migration, proliferation, and invasion in OSCC cells

[84]

–

OSC‑4

–

–

GSK-3β

Rab-5B, Calnexin, Cytochrome-c

AKT

Macrophage-derived exosomes by activating the AKT/GSK-3β pathway could reduce sensitivity to chemotherapeutic agents in OSCC cells

[85]

OSCC (n = 155)

OC3, OECM1, SCC4, SCC25, SAS, CGNHC9

–

–

Activin A, EGFR, SP1, Smad-2/3/4

PI3K/SP1

Activin A via activating the PI3K/SP1 pathway could regulate EGFR was necessary for the carcinogenesis of OSCC

[86]

–

SCC131

Syringic acid

(SRA)

0–45 μm/mL

TNF-α, COX-2, iNOS, IL-6, VEGF, NF-κB

PI3K/AKT

SRA via suppression of the PI3K/AKT/NF-κB axis could induce disruption of MMP, mitochondrial apoptosis, and inhibit cell proliferation and migration

[87]

–

SCC-25

–

–

Alpha-hederin (α-HN), Bax. Bcl-2

PI3K/AKT,

mTOR

α-HN via the PI3K/AKT/mTOR pathway can inhibit cell proliferation, adhesion, invasion and induce apoptosis of OSCC cells

[88]

OSCC (n = 53), BALB/C nude mice

Cal-27,

SCC-25, HIOEC

–

–

miR-210-3p, EFNA3,

N-cadherin,

E-cadherin

PI3K/AKT

Up-regulation of miR-210-3p via the Ephrin-A3/PI3K/AKT pathway could inhibit OSCC cells development and metastasis

[89]

162 OSCC samples with oral submucous fibrosis (OSF), 38 normal buccal mucosa (NBM)

CAL27, HN6, UM1, SCC9, HOK, 293 T

–

–

circEPSTI1,

miR-942-5p, LTBP2, Vimentin,

N-cadherin,

E-cadherin

EMT, PI3K/AKT,

mTOR

The circEPSTI1/miR-942-5p/LTBP2 axis via the EMT and PI3K/AKT/mTOR pathways could promote invasion, migration, and proliferation of OSCC cells

[90]

Male BALB/c nude m

NHOK,

SCC-25,

SCC-9

Genipin

0–400 μM

Survivin, PARP,

Caspase-3, p62, Beclin-1, LC3II/LC3I

PI3K/AKT,

mTOR

Genipin via the PI3K/AKT/mTOR pathway could induce autophagy and apoptosis and suppress the proliferation of OSCC cells

[91]

–

CAL-27, SCC-25

Pristimerin, 5-fluorouracil, cisplatin

0–1 μM,

0–150 μM, 0–20 μM

p21, p27, p53 PARP, Caspase-3,

AKT,

MAPK/ERK

Pristimerin via the MAPK/ERK1/2 and AKT pathways could induce apoptosis and suppress proliferation of OSCC cells more than cisplatin and 5-fluorouracil

[92]

–

HOEC, HN4, HN30, HN6

–

–

PLAC8, PCNA,

c-Myc, GSK-3β,

Cyclin-D1,

E-cadherin, Vimentin

Wnt/β-catenin, PI3K/AKT

PLAC8 via the PI3K/AKT/GSK-3β and Wnt/β-catenin pathways could inhibit carcinogenesis and EMT of OSCC cells

[93]

Cohort,

BALB/c nu/nu female

nude mice

SCC15, CAL27, HOMEC, TSCCA

–

–

lncRNA CASC9, p62,

Bcl-2, Bax, LC3II/LC3I

AKT/mTOR

LncRNA CASC9 via the AKT/mTOR pathway can promote tumoral cell proliferation and progression by suppressing autophagy in OSCC

[94]

86 sample of OSCC and 32 sample of adjacent non-tumor tissues, SPF-grade BALB/c nu/nu female nude mice

HOMEC, TSCCA, SCC15,

CAL27

–

–

Per1, LC3BII/I, Beclin-1, P62,

Bax

AKT/mTOR

Clock gene Per1 via the AKT/mTOR pathway could suppress autophagy and improve cell proliferation in OSCC

[95]

OSCC (n = 92)

SCC4, Cal27, HSC3, HaCaT

–

–

LGALS3BP

PI3K/AKT

LGALS3BP via the PI3K/AKT pathway could promote migration and proliferation of OSCC cells

[96]

–

CAL27,

SCC9

–

–

Notch1,

N‐cadherin, Vimentin,

E‐cadherin,

β‐catenin, P21, Cyclin-D3

EGFR,

PI3K/AKT

Membrane-tethered Notch1 via activating the EGFR/PI3K/AKT axis could exhibit oncogenic property in OSCC

[97]

BALB/cnu/nu nude mice

Cal27

–

–

miR-134,

LAMC2,

GSK-3β, Caspase-9,

Bcl-2, Bax

PI3K/AKT

miR-134 by down-regulating LAMC2 via the PI3K/AKT pathway can suppress cell migration, invasion, and metastases of OSCC cells

[98]

OSCC (n = 134)

SNU1041, SCC25, SCC4, SCC9, hNOK

–

–

lncRNA FTH1P3,

GSK-3β

PI3K/AKT,

Wnt/β-catenin

LncRNA FTH1P3 via the PI3K/AKT/GSK-3β/ Wnt/β-catenin axis could promote migration and invasion in OSCC cells

[99]

8 pairs of OSCC and adjacent normal tissue

SCC-9, TEC,

SCC-25,

TSCCa,

Tca-8113

–

–

miR-194, FoxO3a,

Cyclin-D1,

p21, AGK

PI3K/AKT

miR-194 by reducing the PI3K/AKT/FoxO3a axis could inhibit cell proliferation of OSCC

[100]

OSCC (n = 125)

–

–

–

PTEN

PI3K/AKT, mTOR

Activity of PI3K/AKT pathway is enhanced in the gingival, hard palate, and alveolar ridge SCC. The expression of p-mTOR could be considered as a biomarker of survival in OSCC

[101]

8 pairs of OSCC and normal oral mucosal tissue

–

–

–

c-Met

PI3K/AKT

Carcinoma associated fibroblasts (CAF) via the c-Met/PI3K/AKT pathway could induce lymphangiogenesis in OSCC

[102]

OSCC (n = 56),

BALB/c-nude mice

CAL27, SCC9, HCT 116, 293 T

Cisplatin

0–35 µg/mL

miR-22, KAT6B, Caspase-3,

PARP, p53,

Bcl-2, NF-kB

PI3K/AKT

Overexpression of miR-22 and suppression of KAT6B via the PI3K/AKT/NF-kB pathway can increase the OSCC cells apoptosis by enhancement of the sensitivity of these cells to cisplatin

[103]

–

KB

Sanguinarine

0–2 µM

Caspase-3/8/9,

Fas/FasL, Bid,

Bax, Bcl-2, TRAIL

PI3K/AKT

Sanguinarine via suppressing the PI3K/AKT pathway could induce apoptosis of OSCC cells

[104]

Paraffin-embedded OSCC (n = 90)

–

–

–

GSK-3β

AKT, mTOR

AKT and mTOR proteins could be involved in OSCC progression and modulate the biology of OSCC. In addition, GSK-3β could regulate the mechanism of OSCC dissemination to the cervical lymph node

[105]

–

SCC25, 1483, FeOSCC, K9OSCC

doxorubicin, AD198

0–1 µM,

0–1 µM

cPARP, ERK1/2, p38, GSK-3β, Caspase-3/7

PI3K/AKT

Dox or AD198 as an anthracycline therapy via inhibiting the PI3K/AKT can inhibit cell proliferation in OSCC cells

[106]

OSCC (n = 12), male nude BALB/c mice

SCC4, SCC25, OML1,

OML1-R

–

–

Bax, Caspase-3, Cyclin-D1, CDK4

PI3K/AKT,

mTOR

The PI3K/mTOR pathway is invovled in sensitizing OSCC cells to radiotherapy

[107]

OSCC (n = 25), adjacent non-tumor tissues (n = 5), nude mice

Tca-8113,

KB

–

–

Zinc Finger Protein 703,

c-Myc, GSK-3β, Vimentin, Snail,

N-cadherin,

E-cadherin

PI3K/AKT

Zinc Finger Protein 703 via PI3K/AKT/GSK-3β pathway could promote metastasis and cell proliferation of OSCC

[108]

60 pairs of OSCC and adjacent normal tissue

SCC-25,

HSC3

–

–

Cyclin-D1,

T-cadherin

PI3K/AKT,

mTOR

T-cadherin via inhibiting the PI3K/AKT/mTOR pathway could suppress the proliferation of OSCC

[109]

Male Syrian hamsters

Cal27, LN4, Leuk1

Salvanic acid B

0–600 µM

GLUT1,

HIF-1α

PI3K/AKT

Salvanic acid B via the PI3K/AKT/HIF-1α axis could suppress OSCC malignant transformation by inhibiting aberrant glucose metabolism

[110]

58 pairs of TSCC and adjacent normal tissue

SCC9,

SCC25

–

–

FoxM1,

E-cadherin, Vimentin

c-Met/AKT

FoxM1 via the c-Met/AKT-dependent positive feedback loop pathway could promote EMT, migration, and invasion of TSCC

[111]

female BALB/c nude mice

SCC-25, UM1, UM2, HSC-3, Cal 27

Oridonin

0–10 mg/kg

Bcl-2, Bax,

Caspase-3/9, Cyclin-D1/D3, p21

PI3K/AKT

Oridonin through suppression the PI3K/AKT pathway could suppress proliferation and induce apoptosis and G2/M-phase arrest in OSCC cells

[112]

–

SCC25

Plumbagin

(PLB)

0–5 µM

Bax, Bcl-2,

Caspase-3/9, GSK-3β,

Beclin-1,

LC3-I/II

p38 MAPK, PI3K/AKT,

mTOR

Plumbagin via MAPK and PI3K/AKT/mTOR-mediated pathways could promote autophagy, G2/M arrest, apoptosis, and increase intracellular levels of ROS in TSCC cells

[113]

Female BALB/c mice, 36 pairs of OSCC tissues and adjacent normal tissues

TSC-15, CAL27,

TSCCa, Tca8113,

SCC-4, SCC-25

–

–

PON3, AP-1

PI3K/AKT

PON3 via the PI3K/AKT pathway can promote migration, invasion, and cell proliferation in OSCC cells

[114]