Table 5.

Role of PI3K/AKT pathway in oral squamous cell carcinoma

Samples	Cell Lines	Drug/ phytotherapy	Dose range	Target	Pathway	Function	Refs.
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]