Regulation of Cell Signaling Pathways and Non-Coding RNAs by Baicalein in Different Cancers

Abstract

Landmark discoveries in molecular oncology have provided a wide-angle overview of the heterogenous and therapeutically challenging nature of cancer. The power of modern 'omics' technologies has enabled researchers to deeply and comprehensively characterize molecular mechanisms underlying cellular functions. Interestingly, high-throughput technologies have opened new horizons for the design and scientific fool-proof evaluation of the pharmacological properties of targeted chemical compounds to tactfully control the activities of the oncogenic protein networks. Groundbreaking discoveries have galvanized the expansion of the repertoire of available pharmacopoeia to therapeutically target a myriad of deregulated oncogenic pathways. Natural product research has undergone substantial broadening, and many of the drugs which constitute the backbone of modern pharmaceuticals have been derived from the natural cornucopia. Baicalein has gradually gained attention because of its unique ability to target different oncogenic signal transduction cascades in various cancers. We have partitioned this review into different sub-sections to provide a broader snapshot of the oncogenic pathways regulated by baicalein. In this review, we summarize baicalein-mediated targeting of WNT/β-catenin, AKT/mTOR, JAK/STAT, MAPK, and NOTCH pathways. We also critically analyze how baicalein regulates non-coding RNAs (microRNAs and long non-coding RNAs) in different cancers. Finally, we conceptually interpret baicalein-mediated inhibition of primary and secondary growths in xenografted mice.

Keywords: baicalein; cancer; cell signaling; metastasis; natural products.

Figure 1

(A) Diagrammatic representation of WNT/β-catenin pathway. APC and axin recruited β-catenin, and after sequential phosphorylations of specified amino acid residues in amino-terminal region, β-catenin is poly-ubiquitinated by β-TrCP and tagged for degradation by the proteasomal machinery. (B,C) β-catenin transcriptionally repressed FOXA2. FOXA2 stimulated the expression of lncRNA-NEF. LncRNA-NEF interacted physically with β-catenin and increased the binding of GSK3β with β-catenin and facilitated phosphorylation and degradation of β-catenin by proteasomal machinery. (D) Baicalein also promoted GSK-3β-mediated phosphorylation of β-catenin and subsequent degradation. (E) SNHG1 antagonized miR-3127-5p-mediated targeting of FZD4.

Figure 2

Diagrammatic representation of AKT/mTOR pathway. (A) AKT phosphorylates TSC2 and GTP-loaded RHEB activates mTORC1 (mammalian TOR complex 1). However, TSC1/TSC2-mediated hydrolysis of GTP to GDP switched RHEB from a functionally active GTP-bound state to an inactive GDP-bound state and inhibited the functions of mTOR. (B) DDIT4 has been documented to block the activity of mTORC1 by activation of TSC1/2 complexes. (C,D) Baicalein inhibited mTORC1 (RAPTOR) and mTORC1-mediated phosphorylation of 4EBP1 and S6K.

Figure 3

(A–C) Diagrammatic representation of JAK/STAT pathway. STAT3 upregulated PD-L1 and BCL-XL. Baicalein inactivated JAK/STAT pathway. (D) Baicalein inhibited pulmonary metastasis of breast cancer cells in animal model.

Figure 4

(A) Ezrin is a target gene of tumor suppressor miR-183. miR-183 inhibited tumorigenesis but ezrin promoted tumorigenesis. (B) miR-17-5p and miR-424-3p are oncogenic miRNAs. These miRNAs targeted PTEN. Tumor suppressor lncRNA blocked miR-17-5p-mediated targeting of PTEN and inhibited carcinogenesis. (C) BDLNR physically associated with YBX1 and promoted its binding to PIK3CA promoter and facilitated cancer progression.

Figure 5

(A) Baicalein induced degradation of HIF-1α by PHD and pVHL. (B) HIF-1α and HIF-1β transcriptionally upregulated VEGF. However, baicalein blocked HIF-1α-mediated VEGF expression. (C) AML1-ETO worked synchronously with HDAC1 and transcriptionally repressed the target genes.