Table 2 Curcumin targets multiple levels of the cancer stem cell related signaling pathways

Hedgehog signaling

Receptor: Curcumin treatment led to a decrease in Shh and PTCH1 at protein level, triggering apoptosis in medulloblastoma cells

[92, 97, 98]

Downstream effector: Down-regulation of Gli1 expression in curcumin treated-brain tumour cells

Transcriptional activity: Reduction in Gli1 mRNA level, therefore it downregulates Gli1-responsive genes

Notch signaling

Receptor: (1) Curcumin downregulated Notch-1 at transcriptional level, which subsequently lowered the abundance of the receptor

[88, 89, 99]

(2) Curcumin suppressed Notch-1 activation through down-regulation of a key component of the γ-secretase protein complex in esophageal cancer cells

Transcriptional activity: Curcumin inactivated nuclear factor-kB DNA-binding activity in oral carcinoma CAL-27 cells, thus targeting the cancer cells by activating apoptosis and reducing cell growth and invasion

PI3K/Akt signaling

Intermediate transducer: Curcumin inhibited of the activation of PI3K/AKT/mTOR and its related pathways at multiple regulatory effectors via modulation of their phosphorylation status[Akt (T308 and S473), FoxO1 (S256), GSK3β (S9), tuberin/TSC2 (T1462), mTOR (S2448/2481), p70 S6K (T389), S6 (S235/236), 4E-BP1 (S37/46), eIF4G (S1108)]

[85, 87, 93, 94]

Transcriptional activity: Curcumin decreased total expression of mTOR, Raptor and Rictor protein and mRNA levels

Wnt/β-catenin signaling

Receptor: Frizzled-1 (the receptor of Wnt proteins) was inhibited in curcumin- treated human head and neck squamous cell carcinoma cell line mda 1986

[90, 91, 92, 95, 96]

Downstream effector: Curcumin induced caspase-3-mediated cleavage of β -catenin, leading to inactivation of Wnt/β-catenin signaling

Transcriptional activity: Curcumin reduced β-catenin/tcf transcriptional activity via downregulation of β-catenin and its positive regulator, p300