FoxM1 (forkhead box protein M1) protein is a member of the Fox (forkhead box) family of transcription factors with known roles in regulating cell cycle progression. FOXM1 is a master regulator of cancer cell growth and is overexpressed in a majority of cancers, while its expression usually low in normal cells. Elevated FoxM1 expression is found in cancers of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system. In addition, FoxM1 may drive tumor invasion, angiogenesis, and metastasis. For these reasons, FoxM1 is an attractive target for anticancer drugs such as doxorubicin, epirubicin and cisplatin.
FoxM1 is a downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt3a increases the level and nuclear translocation of FoxM1, which binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. FoxM1-β-catenin interaction controls Wnt target gene expression and thus, FoxM1 mutations that disrupt the FoxM1-β-catenin interaction (or FoxM1 nuclear import) prevent β-catenin nuclear accumulation in tumor cells. Targeting FOXM1 in mono- or combination therapy has promising therapeutic benefits for the treatment of cancer.
AMPK (AMP-activated protein kinase) is a metabolic sensor with a key role in metabolic disorders and in cancer. AMPK is also a metabolic tumor suppressor. Because AMPK activation inhibits most biosynthetic pathways and causes cell cycle arrest, it should also have a cytostatic, tumor suppressor effect. It has been shown that activation of AMPK reduces cancer cell growth through blocking the Wnt/β-catenin signaling activity. Increased AMPK activity suppresses FoxM1 expression. Bitter melon extract (BME) is a natural AMPK activator. BME has been found to possess anti-cancer activities via its ability to increase AMPK activity.
The tyrosine kinase receptor, HER2 is a crucial prognostic marker and therapeutic target for breast cancer and the hormone EGF (epidermal growth factor) normally activates it. HER2-overexpressing metastatic breast cancer is extremely resistant to treatment. The biotech company Genentech developed a monoclonal antibody called Herceptin (trastuzumab) that interferes with the HER2/neu receptor.
FoxM1 mediates resistance to Herceptin and chemotherapy agents such as paclitaxel. Genistein, a major component of soybean products, is considered a general or broad-base tyrosine kinase inhibitor. Genistein is as effective as Herceptin in inhibiting the growth of advanced breast cancer cells. Both Genistein and DIM (3,3′-diindolylmethane) inhibit FoxM1 activation in cancer cells leading to apoptotic cell death. DIM is a natural compound present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts, cauliflower and kale.
Emerging evidence suggests that crosstalk between the androgen receptor (AR) and β-catenin is critical for the development of prostate cancer and the progression of prostate cancer to castrate-resistant stage (also called androgen-independent or hormone refractory). Together with the increased expression of AR and β-catenin, there is increased nuclear colocalization and interaction of endogenous AR and β-catenin in castrate-resistant prostate cancer. AR promotes translocation of cytoplasmic β-catenin to the nucleus and thereby increases AR transcription and regulates Wnt. Therefore, modulation of β-catenin signaling attenuates the aggressive behavior of prostate cancer cells and induces apoptosis.
A recent study suggested that lowering SCD1 (Stearoyl-CoA desaturase-1) expression leads to a decrease of β-catenin amounts within the nucleus and to inhibition of its transactivation capacity. SCD1 is an endoplasmic reticulum anchored enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly palmytoleyl-CoA and oleyl-CoA. SCD is an important metabolic control point in the fatty acid synthesis pathway that is essential for cancer cell viability. Cancer cells are sensitive to loss SCD function. SCD1 silencing also inhibits GSK-3 phosphorylation and impairs the epithelial to mesenchymal transition-like behavior of the cells, a characteristic of metastatic cancer.
In the previous article, we discussed a function for SCD1 in the modulation of signaling processes related to cancer cell proliferation and survival and how SCD1 inhibition causes cancer cell death. We now know that sterculic oil and omega-3 polyunsatuted fatty acids act as inhibitors of SCD1.
β-catenin signaling is also associated with drug resistance and its inhibition is associated with increased multiple drugs cytotoxicity in various cancers.
We have many β-catenin signaling inhibitors at our disposal. Methylseleninic acid (MSA), an organic selenium compound, reduces β-catenin protein levels in cancer cells and reduces/delays cancer metastasis. Moreover, MSA accelerates the degradation of β-catenin and activates GSK-3β. The enzyme GSK-3β forms a complex with β-catenin and promotes its degradation in the proteasome. MSA acts on the inhibition of β-catenin/TCF pathway.
However, GSK-3β is involved in multiple signaling pathways and has many phosphorylation targets. It should therefore not be surprising that GSK-3β has both pro- and antiapoptotic roles in cancer. Lithium is an inhibitor of GSK-3β activity. Thus, lithium activates canonical Wnt signalling by GSK-3β inhibition, which in turn stabilizes cytosolic free beta-catenin, and inhibits β-catenin degradation. Indeed, lithium acts as a double-edged sword in cancer treatment. It is not easy to safely kill the cancer cells.
Berberine is a bitter-tasting, yellow, plant alkaloid with a long history of medicinal use. Berberine is present in the roots, rhizomes and stem bark of various plants including goldenseal (Hydrastis canadensis), Oregon grape (Berberis aquifolium), and barberry (Berberis vulgaris). Berberine reduces cellular levels of active β-catenin and inhibits β-catenin transcriptional activity. Silymarin, honokiol, lupeol, genistein, gugulipid, resveratrol, quercetin, EGCG, lycopene, sulforaphane, ellagic acid, Vitamin D, and omega-3-polyunsaturated fatty acids also antagonize or modulate Wnt/β-catenin signaling. We believe that these natural agents that are non-toxic in nature could be used either alone or in combination with conventional therapeutics for the prevention and/or treatment of a variety of cancers.