Prevention of Wogonin on Colorectal Cancer Tumorigenesis by Regulating p53 Nuclear Translocation

Abstract

The tumor suppressor protein p53 plays an important role in the development and progression of colon cancer, and the subcellular organelle localization directly affects its function. Wogonin (5,7-dihydroxy-8-methoxyflavone), a mono-flavonoid extracted from root of Scutellaria baicalensis Georgi, possesses acceptable toxicity and has been used in colorectal cancer (CRC) chemoprevention in pre-clinical trials by oncologist. However, the underlying anti-colon cancer mechanisms of wogonin are not yet fully understood. In the present study, the effect of wogonin on the initiation and development of colitis-associated cancer through p53 nuclear translocation was explored. AOM-DSS CRC animal model and human CRC HCT-116 cell model were used to evaluate the in vivo and in vitro anti-colon cancer action of wogonin. We observed that wogonin showed a dramaticlly preventive effect on colon cancer. Our results showed that wogonin caused apoptotic cell death in human CRC HCT-116 cell through increased endoplasmic reticulum (ER) stress. Meanwhile, excessive ER stress facilitated the cytoplasmic localization of p53 through increasing phosphor-p53 at S315 and S376 sites, induced caspase-dependent apoptosis and inhibited autophagy. Furthermore, we verified the chemoprevention effect and toxicity of wogonin in vivo by utilizing an AOM-DSS colon cancer animal model. We found that wogonin not only reduced tumor multiplicity, preserved colon length to normal (6.79 ± 0.34 to 7.41 ± 0.56, P < 0.05) but also didn’t induce side effects on various organs. In conclusion, these results explain the anti-tumor effect of wogonin in CRC and suggest wogonin as a potential therapeutic candidate for the therapeutic strategy in CRC treatment.

The Therapeutic Potential of Wogonin Observed in Preclinical Studies

“…As described previously, wogonin displays several important biological properties highly relevant to human health improvement. Probably, the most explored are its antitumor features; it strongly induces apoptosis of different cancer cells, including leukemia, multiple myeloma, lymphoma, and ovarian cancer [9,[15][16][17][18][19][20][21].…”

“…e role of wogonin against colorectal cancer (CRC) has not yet been fully established. However, the outcomes of a preclinical study displayed that wogonin treatment induces apoptosis in human CRC HCT-116 cell by accelerating the endoplasmic reticulum (ER) stress by localization of p53 through activation of phosphor-p53 [21]. Moreover wogonin has been seen inhibiting the tumor angiogenesis through the degradation of HIF-1α [25], inhibiting the proliferation of human CRC cells when introducing autophagy, apoptosis, and cell cycle arrest at G2/M through the modulation of the marking PI3K/AKT and signal transducer and activator of transcription (STAT3) [26].…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…2) is a plant flavonoid extracted from roots of Scutellaria baicalensis, Scutellaria amoena and Scutellaria rivularis, and stem of Anodendron affine Druce, and has many pharmacological effects including anti-viral, anti-oxidative, anti-inflammatory, anti-cancer and neuroprotective activities [702][703][704][705]. It has various anti-cancer effects in many cancers, including lung, breast, head and neck, gastric and colorectal cancers, glioma, leukemia, lymphoma, and osteosarcoma, through the induction of apoptosis and cell cycle arrest, and inhibition of cell growth, migration, invasion, and angiogenesis [706][707][708][709][710][711][712][713][714][715][716].…”

Colorectal Cancer Stem Cells in the Progression to Liver Metastasis

“…TP53 acquired mutations have been shown to affect a plethora of cancers including colon, stomach, breast, lung, brain, and esophageal cancers, and estimations indicate that over 50% of all cancer cases contain TP53 mutations (154)(155)(156)(157)(158)(159). In CRC, missense mutations in the DNA binding domain lead to its oncogenicity.…”