Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer

Abstract

Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.

Keywords: autophagy; autophagy inhibitors; colorectal cancer; lysosome; natural products.

Figure 1

Molecular mechanisms of autophagy in mammalian cells.

Figure 2

Structures of the natural compounds for the treatment of colorectal cancer by targeting the autophagy pathway.

Figure 3

The relationship between the natural products targeting the major signaling pathways that modulate autophagy and colon cancer. Regulation of autophagy induction by the Unc-51-like kinase 1 (ULK1) complex is mediated by the PI3K/AKT pathway. mTOR is negatively regulated by LKB1/AMPK, while cytoplasmic p53 stimulates mTOR by blocking AMPK. Autophagy is also activated by the RAS/RAF/ERK pathway via Beclin-1 to facilitate nucleation. Expression of Atg5 regulates phagophore development, which is induced by reactive oxygen species, leads to the activation of c-Jun NH2-terminal kinases (JNKs). Bufalin could induce oxidative stress by activating JNK. JNK has the ability to phosphorylate Bcl-2 and liberate Beclin 1, thereby promoting autophagy. Alternately, JNK can stimulate the phosphorylation of c-jun; which promotes the generation of AP-1 that enhances the expression of numerous genes, including Beclin 1, Atg5, and Atg7. Beclin 1 and Atg 5 have the potential to induce autophagy. In contrast, the Wnt/β-catenin pathway activates and recruits β-catenin protein into the nucleus, thereby directly regulating autophagy. Without Wnt, a destruction complex degrades β-catenin in the canonical Wnt pathway, preventing cytoplasmic accumulation. The following proteins comprise this destruction complex: Axin, glycogen synthase kinase 3β (GSK3β), adenomatosis polyposis coli (APC), and casein kinase 1α (CK1α). On the other hand, Beclin 1 and some other autophagy-linked protein expression levels are increased by the IKKα/β and NF-κB pathways, inducing autophagy. In addition, NF-κB signaling can inhibit autophagy by overexpressing autophagy repressors such as Bcl-2/Xl and BNIP3. Natural products targeting the key signaling pathways that control autophagy in colon cancer. T-arrows represent inhibition, whereas arrows represent activation.