Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Abstract

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

Keywords: combination therapy; curcumin; polyphenol; receptor tyrosine kinase; signaling pathway; tyrosine kinase inhibitor.

FIGURE 1

Abnormal RTK activation mechanisms. From top left: overexpression, gain-of-function mutations, autocrine activation, chromosomal translocation/fusion protein. Created with BioRender.com.

FIGURE 2

Overview of curcumin-inhibition of RTKs and downstream MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathway components. Abbreviations: RTK: Receptor tyrosine kinase; CUR: Curcumin, EGFR: Epidermal growth factor receptor, TLR4: Toll-like receptor 4, c-MET: Mesenchymal epithelial transition factor/Hepatocyte growth factor receptor; FGFR: Fibroblast growth factor receptor; IGF-1R: The insulin-like growth factor 1 receptor; PDGFR: Platelet-derived growth factor receptor; VEGFR: Vascular endothelial growth factor receptor; TKD: Tyrosine kinase domain; Rac: Ras-related C3 botulinum toxin substrate; ASK1: Apoptosis signal-regulating kinase 1; C/EBPα: CCAAT/enhancer-binding protein alpha; JNK: c-Jun N-terminal kinases; AP-1: Activator protein 1; Ras: Rat sarcoma virus protein; Raf: Rapidly accelerated fibrosarcoma protein; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; PPARγ: Peroxisome proliferator-activated receptor γ; COX2: Cyclooxygenase-2; PI3K: Phosphoinositide 3-kinase; PTEN: Phosphatase and tensin homolog; Akt: Ak strain transforming; IKK: Inhibitor of nuclear factor kappa B kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; FOXO: Forkhead box transcription factors; GSK3B: Glycogen synthase kinase 3 beta; Mtorc1: Mechanistic target of rapamycin complex 1; 4EBP1: Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; S6K: Ribosomal protein S6 kinase; HIF-α: Hypoxia-inducible factor alpha; JAK: Janus kinase; STAT: Signal transducer and activator of transcription. Created with BioRender.com.