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Can spices modify the cancer cell signaling pathway?

How do cells communicate?

Cells have receptors that bind to signaling molecules and initiate a physiological response. Different receptors are specific for different molecules. For instance, dopamine receptors bind dopamine, insulin receptors bind insulin, and oestrogen receptors bind oestrogen. There are hundreds of receptors found on each cell. Receptors are generally transmembrane proteins which, after binding to signaling molecules outside the cell, transmit or transduce the signal through a sequence of molecular switches to internal signaling pathways. Because membrane receptors interact with both extracellular signals and molecules within the cell they permit signaling molecules to affect cell function without actually entering the cell. This is important because most signaling molecules are either too big or too charged to cross a cell's plasma membrane. Some receptors exist within the cell and they typically bind to molecules that can pass through the plasma membrane.

There are many different ways for cells to communicate with each other and the outside environment. They may communicate directly through juxtacrine signaling, over short distances through paracrine signaling and over large distances through endocrine signaling. Additionally, some cells require cell-to-cell contact in order for communication to occur. For this there are gap junctions which connect the cytoplasm of two cells together. In most cases, a molecule carries the signal from one cell and receptors on the other cell bind to the signal molecule thereby allowing communication.

The end result of cell communication is the activation of transcription factors and the initiation of gene expression. In normal cells the cell signaling pathway is tightly regulated. However, in cancer cells regulation fails and a dysregulated signal transduction increases the do proliferate' and do not die' signals, while decreasing the do die' signal.

The cell signaling pathway

The cell cycle is controlled by a series of signaling events consisting of positive and negative regulators that drive cell reproduction and apoptosis. The cell signaling pathway consists of growth factors, receptors and transcription factors (see Figure 1).

Growth factors

Growth factors are soluble extracellular proteins that bind to receptors on the outside of the cell and work through their specific receptors to mediate signals (see Figure 2). These receptor proteins span the width of the plasma membrane and are therefore able to transfer signals from growth factors outside the cells to structures within the cells. Once inside the cell, the signal generated at the receptor is transferred to the nucleus by kinase enzymes and other proteins. This binding creates a chemical signal that is transmitted to the cell's nucleus through a series of steps known as signal transduction. The purpose of this process is the activation of transcription factors and the initiation of gene expression. In addition to growth factors, the process of cell-to-cell contact at the cell's surface can instigate signal transduction and generating signals which are then transferred to the nucleus. The three primary proteins that mediate signal transduction are protein tyrosine kinase (PTK), protein kinase (PK) and the ras protein. Receptors tyrosine kinases are the high affinity cell surface receptors for many polypeptides' growth factors. In selected cancers, activating mutations in a tyrosine kinase initiate the transformation from a benign to a malignant state.

The signals that instruct a cell to live or to proliferate generally come from outside the cell, usually from contact with growth factors or from contact, or lack of it, with other cells and tissues. A fine example is offered by the liver cells that are placed in very close contact with one another.

The liver cell does not undergo apoptosis, since the close contact with other cells continually generate a do not die' signal, with very few do proliferate' signals. Similarly to liver cells, cancer cells are stimulated to proliferate and do not undergo apoptosis. However, unlike liver cells, cancer cells proliferation continues indefinitely because of the ability to produce their own growth factors (see Table 1).

Furthermore, cancer cells are also able to express the overproduction of proteins aimed at protecting against apoptosis, a process that can lead to malfunctions or underproduction of proteins inducing apoptosis. All of the above factors are intended to override the complex control that normally regulates proliferation and survival and confer immortality to cancer cell. (1)

Transcription factors

Transcription factors regulate the expression of genes within a cell and ultimately control cell behavior. Thousands of these transcription factors are frequently locked in an on' position in cancer cells; while the transcription factors are shut off, a cancer cell will generally stop growing or begin to die. A number of oncogenic transcription factors such as AP-1, NF-kB, STAT3, and others are overactivated in human cancer and thus may present promising targets for targeted treatment in cancer medicine. (2)

NF-k, so far the most well-known and understood transcription factor, has a very important role in the development and progression of cancer because it regulates more than 500 genes involved in inflammation, cell proliferation, cell survival, invasion, angiogenesis and metastasis. NF-kB is a nuclear factor that binds to the enhancer region of the kB chain of immunoglobulin in B cells. Upon activation, it is trans-located to the nucleus where it induces the expression of target genes. 3 Many of the target genes are critical to the establishment of the early and late stages of aggressive cancers which require metastasis and angiogenesis for survival. Significantly, spice-derived nutraceauticals have been shown to exert anticancer effects through the suppression of NF-kB. (4) Curcumin as well as other curcuminoids from turmeric mediate their therapeutic effects by regulating NF-kB that, in turn, regulates gene products cyclooxygenase-2 (COX 2), cyclin D1, adhesion molecules, MMPs, inducible nitric oxide synthase and tumor necrosis factor (TNF) (5) (see Figure 3). Other spice-derived phytochemicals, such as capsaicin, cardamonin, dibenzoylmethane, diosgenin, gambogic acid, gingerol, thyoquinone, urosolic acid and zerumbone have been show the ability to suppress NF-kB activation in a similar manner. (6)

STAT3 is another transcription factor that selectively binds to interleukin (IL)-6 to stimulate hepatocytes. STAT3 is normally present in the cytoplasm of most cells and, in response to inflammation and growth factor, it undergoes sequential tyrosine phosphorylation, nuclear translocation and gene transcription. Janus-activated kinase 1, 2 and 3 are protein kinases that have been shown to specifically cause phosporylation of STAT3. These kinases are associated with cellular transformation, survival, proliferation, angiogenesis and metastasis. STAT3 is constitutively active in most tumour cells and interestingly, its activation has been associated with chemoresistance and radioresistance. As reported by Bharti et al. (7) curcumin has the potential to suppress STAT3 activation in human multiple myeloma, glioma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, T-cell leukemia, ovarian cancer, endometrial cancer and head and neck cancer. (8) The researchers have shown that capsaicin inhibits the janus-activated kinase 1 and c-SRC, which are both implicated in STAT3 activation. In glial tumours, capsaicin was reported to down regulate IL-6. Additionally, ursolic acid was found to down regulate STAT3 antiapototic genes such as Bcl-2 and surviving. (9)

Aberrant EGFR signaling is predominantly expressed in breast cancer. Since the discovery of EGF in the 1960s and its receptor in the 1980s, the understanding of the EGF/EGFR has significantly advanced. EGFR belongs to a family of receptors, known as HER, composed of four related proteins: EGFR, ERBB2, ERBB3 and ERBB4. Curcumin has been found to inhibit the ligand-stimulated activation of EGFR in numerous cancer cells including breast, colon, prostate, lung and head and neck cancers. (10) The beneficial effects of capsaicin has been illustrated by Thoennissen et al in a research study that demonstrates that it may cause cell-cycle arrest and apoptosis in ER-positive and negative breast cancer cells by modulating the EGFR/HER-2 pathway. (11)

VEGF is a signaling protein produced by the cell to stimulate the growth of new blood vessels. Its receptor VEGFR is involved in both vasculogenesis and angiogenesis (see Figure 4). One of the spice-derived nutraceauticals to have shown to downregulate VEGF signaling is Gingerol. Ganbogic acid has also been shown to be effective in inhibiting VEGFR signaling, thus preventing angiogenesis and prostate tumour-growth. (12)

Insulin-like growth factors (IGFs) exert multiple effects on glucose, fat and protein metabolism. IGFs also play an important role in regulating cell proliferation, differentiation, apoptosis and transformation. Some of the key pathways include the phosphorylation of mitogen-activated protein kinase (MAPK) and a subsequent increase in proliferation, activation of protein kinase and modulation of mammalian target of rapamycin (mTOR). (13) This process results in translational adaptation. IGF has been implicated in several human cancers, including epithelial cancer, sarcoma, multiple myeloma, melanoma and childhood cancers. Furthermore, high circulating IGF levels have been associated with an increased risk of developing breast, prostate, lung, colorectal and bladder cancers. A study conducted by Xia et al has been shown curcumin to down regulate the secretion of IGF. (14)

m-TOR is a key regulator of various cellular processes needed for growth, cell-cycle progression and cell metabolism. It is considered to be one of the most commonly activated signaling pathway in human cancer and it plays a crucial role in cell growth, proliferation, motility, survival, apoptosis, autophagy and angiogenesis. Rapamycin, first isolated from the soil of Rapa Nui (Easter Island) is the first potent inhibitor of this pathway which has been shown to play a critical role in cell growth, proliferation, motility, survival, apoptosis, autophagy and angiogenesis. (15)

The beneficial effects of curcumin on mTOR pathway have been demonstrated in a variety of cancer cell lines (Table 2). Curcumin has been shown to exhibit anticancer activity by inhibition of mTOR pathway in adenoid cystic carcinoma, intestinal microvascular endothelial cells, head and neck squamous cells carcinoma and prostate cancer. (16)

Conclusion

Considerable data regarding the beneficial effects of spice nutraceauticals on prevention and treatment of cancer in preclinical settings are available. However, clinical trials and further studies on these nutraceauticals are encouraged to better elucidate and understand their efficacy in the treatment and prevention of human cancers.

References

(1.) Perona R. Cell signalling: growth factors and tyrosine kinase receptors. Clinical Translational Oncology. 2006;8(2):77-82.

(2.) Matthews CP., Colburn NH., Young MR: AP-1 a target for cancer prevention. Current Cancer Drug Targets 7. 2007: 317-324

(3.) Lee JI., Burckart GJ. Nuclear Factor Kappa B: Important Transcription Factor and Therapeutic Target. Journal of Clinical Pharmacology. 1998 :38(11): 981-993

(4.) Aggarwal BB. Targeting Inflammation-Induced Obesity and Metabolic Diseases by Curcumin and Other Nutraceuticals. Annual Review Nutrition. 2010 30: 173-199

(5.) Notarbartolo M., Poma P., Perri D., Dusonchet L. Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression Cancer Letters. 2005 24 (1): 53-65

(6.) Singh S., Naturajan K., Aggarwal BB. Capsaicin is a potent inhibitor of nuclear transcription factor kappa B activation by diverse agents. J Immunology 157, 44124420, 1996

(7.) Bharti AC., Donato N. Curcumin inhibits constitutive and IL-6 inducible STAT3 phosphorylation in human multiple myeloma cell. J Immunology 171,38633871, 2003

(8.) Aggarwal BB, Vijayalekshmi RV., Sung B. Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: ShortTerm Friend, Long-Term Foe. Clinical Cancer Research. 2009 15; 425

(9.) Shishodia S., Majumdar S., Banerjee S. Ursolic acid inhibits nuclear factor kappa B activation induced by carcinogenic agents through suppression of NF-kB alpha kinase and p65 phosphorylation. Cancer Research 2003. 63: 4375-4383

(10.) Aggarwal BB., Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical Pharmacology. 2006: 71:1397-1421

(11.) Thoennissen NH, O'Kelly J, Lu D, Iwanski GB, La DT, Abbassi S, et al. Capsaicin causes cell cycle arrest and apoptosis in ER-positive and-negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene. 2010:29(2):285-96.

(12.) Pandey MK., Sung B., Ahn KS. Gambogic acid, a novel ligand for transferrin receptors, potentiates TNF-induced apoptosis through modulation of the nuclear factor kappa-B signaling pathway. Blood 2007. 110: 3517-3525

(13.) Yamada Y, Kohashi K, Fushimi F. Activation of the Akt-mTOR pathway and receptor tyrosine kinase in patients with solitary fibrous tumor. Cancer 2013: 18:10

(14.) Xia Y, Jin L, Zhang B, Xue H, Li Q, Xu Y. The potentiation of curcumin on insulin-like growth factor-1 action in MCF-7 human breast carcinoma cells. Life Science 2007. 80(23):2161-9.

(15.) Hidalgo M., Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 2000:19(56):6680-6686

(16.) Sung B., Prasad A., Yadav VR. Cancer Cell Signaling Pathways Targeted by Spice-Derived Nutraceuticals. Nutrition and Cancer. 2011.64(2):173-197

Manuela Malaguti-Boyle | PhD Candidate, BHSc (Comp Med), ND. Email: Manuela.boyle@sky.com, www.cliniciansolutions.com

Table 1. Growth factors

Growth Factors              Comments

Epidermal Growth Factor     The EGF receptor is overexpressed in most
                              human cancers. The EGF receptor binding
                              can increase cell proliferation, cell
                              motility, invasion and metastasis.
Fibroblast Growth Factor    FGF can stimulate proliferation of many
                              cell types and is involved in
                              angiogenesis.
Insulin-like Growth         It stimulates cell proliferation and share
  Factor                      many properties with insulin, except
                              they do not stimulate glucose
                              utilization. IGF receptors occur on a
                              variety of human tumours, including
                              breast cancer.
Platelet derived Growth     It stimulates the proliferation of
  Factors                     epithelial cells and other cells. It is
                              released by platelets to stimulate wound
                              healing and can also be produced by
                              tumour cells.
Transforming Growth         It is a multifunctional protein that
  Factor-beta                 controls proliferation, differentiation
                              and other cell activities. It can either
                              increase or decrease proliferation,
                              depending on the cell type and
                              conditions. In the early stages of
                              transformation, TGF-beta inhibits
                              proliferation of several cell types;
                              however in advanced cancers it can
                              become resistant to its
                              growth-inhibitory actions.
Vascular endothelia         VEGF induces endothelial proliferation and
  growth factor               vascular permeability factor. It plays a
                              crucial role in angiogenesis.
Transforming Growth         TGF-alpha is produces by macrophages,
  Factor-alpha                brain cells and other cells. It induces
                              angiogenesis.

Growth Factors              Receptor type

Epidermal Growth Factor     Protein tyrosine kinase

Fibroblast Growth Factor    Protein tyrosine kinase

Insulin-like Growth         Protein tyrosine kinase
  Factor

Platelet derived Growth     Protein tyrosine kinase
  Factors

Transforming Growth         Protein tyrosine kinase
  Factor-beta

Vascular endothelia         Protein tyrosine kinase
  growth factor

Transforming Growth         Protein tyrosine kinase
  Factor-alpha

Table 2. A list of clinical trials with
spice-derived nutraceauticals in cancer patients

Cancer              Spice        dose                       Patients

Colorectal          Curcumin     36-180mg/day x 120 days    15
Metastatic breast   Curcumin     500-8,000mg/day x 7 days   14
  cancer
Multiple myeloma    Curcumin     2-12 g/day                 24
Prostate cancer     Curcumin     100mg/day x 180 days       100
Various primary     Ginger       250mg x 2/day x 3 days     28
  sites               extracts

Pancreatic          Capsaicin    0.075% Cream x 56 days     49
Lung                Anethole     75mg/day x 6 months        112

Cancer              End point

Colorectal          Decreased lymphocytic GST
Metastatic breast   Significant reduction (57%)
  cancer
Multiple myeloma    Inhibited NF-kB, COX-2 and STAT3
Prostate cancer     Decreased PSA levels
Various primary     Reduced nausea by chemotherapy;
  sites               reduced use of antiemetic
                      medications
Pancreatic          Reduced pain
Lung                Lowered progression rate
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Author:Malaguti-Boyle, Manuela
Publication:Journal of the Australian Traditional-Medicine Society
Geographic Code:8AUST
Date:Mar 1, 2014
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