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Cervical cancer is the second most prevalent and the fifth most deadly malignancy seen in women worldwide. It accounts for about 500 000 new cases and over 270 000 deaths estimated every year.[2, 3] The treatment of cervical cancer varies worldwide, largely due to large variances in disease burden in developed and developing nations, access to surgeons skilled in radical pelvic surgery, and the emergence of ‘fertility-sparing therapy’ in developed nations. Current approaches for treating cervical cancer have limited success, with an estimated 5-year survival rate of 60% for women with cervical cancer.
Because cervical cancers are radiosensitive, radiation may be used in all stages where surgical options do not exist. Chemotherapy and radiotherapy could have a synergistic effect.5 Cisplatin is believed to augment the effects of radiation by inhibiting the repair of radiation-induced sublethal damage and by sensitizing hypoxic cells to radiation.6 The use of a combination of two chemotherapy drugs of topotecan and cisplatin are recommended for women with late-stage cervical cancer by the US Food and Drug Administration; however, combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side-effects. There is an urgent need to develop new therapies for cervical cancer because of their poor prognosis.
Epidermal growth factor (EGF) is a growth factor that stimulates cell growth, proliferation, and differentiation by binding to its receptor EGFR. When EGF and its relatives bind the erythroblastic leukemia viral oncogene homolog (ErbB) family of receptors, they trigger a rich network of signaling pathways, culminating in responses ranging from cell division to death, motility to adhesion. Dysregulated activation of this network has been implicated in diverse types of human cancer, including cervical cancer.
In the present study, we sought to explore the mechanisms of cervical carcinoma response to EGF, and then identify biologically active small molecules capable of targeting the sub-pathways, which were dysregulated in cervical cancer cells in the response to EGF. Candidate agents identified by our approach may provide the groundwork for a combination therapy approach for cervical cancer; however, further evaluation for their potential use in the treatment of cervical cancer is still needed.
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In this study, we used the gene expression profile downloaded from GEO to explore the mechanisms of cervical cancer cells' response to EGF. Furthermore, we showed the utility of using bioinformatics analysis for the identification of new therapeutics for cervical cancer. A total of 617 genes were identified differentially expressed after treatment with EGF in cervical cancer cells. Sub-pathway mining results showed that three entire pathways, MAPK signaling pathway, p53 signaling pathway and pathways in cancer, were dysregulated after treatment with EGF. A total of 49 small molecules were identified which may play a role in perturbing the response to EGF of cervical cancer cells.
Current approaches typically study entire pathways, whether by singular enrichment analysis or by gene set enrichment analysis; however, sub-pathways analysis may be more suitable than entire pathways for identification of drug response. We identified that a total of 13 sub-pathways were dysregulated in the response to EGF, including seven sub-pathways in MAPK signaling pathway, five sub-pathways in p53 signaling pathway and one sub-pathway in pathways in cancer. Our results suggest that EGF could promote cervical cancer cell proliferation through triggering the dysregulation of certain sub-pathways in MAPK signaling pathway, p53 signaling pathway and pathways in cancer. Our results are consistent with a previous study that determined that a number of MAPK phosphatases undergo transcriptional induction after growth factor activation.
The MAPK pathways transduce a large variety of external signals, leading to a wide range of cellular responses, including cell proliferation, differentiation, inflammation and apoptosis.17 The dysregulation of the MAPK signaling pathway has been implicated in a large variety of pathological conditions, including cancer, ischemic heart disease and inflammatory disorders, and has therefore been appreciated as an attractive candidate for drug development. Moreover, MAPK inhibitors have been used in combination with other immunosuppressive drugs, including biological therapy.
Research over the past 3 decades has identified that p53 is a transcription factor that controls a major pathway protecting cells from malignant transformation.[19, 20] This anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated anti-cancer drug development efforts to (re-)activate p53 in established tumors.
EGF is part of a complex network of growth factors and receptors that together help to modulate the growth of cells.22 As such, targeting the EGF receptors, or the cellular signaling pathways activated by EGF, is a rational approach to identifying new therapeutic targets. Early in the 1980s, Sato et al. hypothesized that a monoclonal antibody that binds to EGF receptors and that can block the binding of EGF might prevent cell proliferation by inhibiting the signal transduction pathways that depend on activation of the EGF receptor.[23-25]
There are several important implications of this work. The identification of a group of small molecules with potential therapeutic efficacy for cervical cancer is an important observation. A total of 49 molecules were identified as having common sub-pathways with EGF response of cervical cancer cells. Text-mining results showed that ciclopirox, etoposide and thioridazine were suggested to have anti-cancer effect in cervical cancer.[26-31] These small molecules should be evaluated further with a high level of concern. Besides, some small molecules were suggested to have an anti-cancer effect in other cancer lines, such as parthenolide, pyrvinium and ciclopirox.
Parthenolide, one of the major sesquiterpene lactones found in the medicinal plant, feverfew (Tanacetum parthenium), is utilized primarily for prevention and/or relief of migraine as well as for anti-inflammatory effects in arthritis.[32, 33] More recently, parthenolide has been found to have several other properties, including antitumor activity, inhibition of DNA synthesis, and inhibition of cell proliferation in different cancer cell lines, such as colorectal cancer, hepatoma, cholangiocarcinoma, and pancreatic cancer.[34-39] In addition, parthenolide sensitizes cancer cells to other antitumor agents.[40-42]
Furthermore, pyrvinium has also been reported to display anticancer activity. Pyrvinium was an old anthelminthic medicine. Esumi et al. recently reported that it was preferentially toxic to glucose-starved cancer cells and had anti-cancer activity in a hypovascular Panc-1 pancreatic cancer model, known to be resistant to hypoglycemia. Ciclopirox is a synthetic antifungal agent that has clinically been used to treat mycoses of the skin and nails for 20 years.[44-46] Most recent studies have revealed that ciclopirox displays preclinical anticancer activity against breast tumors and may be a potential antitumor agent.
The most significant small molecules of our result have been reported to display anticancer activity. Thus, our results are credible. The further study of the rest of the 49 small molecules will provide the groundwork for developing new therapies for treatment of cervical cancer.
In conclusion, our study showed that EGF could promote cervical cancer cell proliferation through triggering the dysregulation of certain sub-pathways in the MAPK signaling pathway, the p53 signaling pathway and pathways in cancer. Furthermore, our bioinformatics analysis revealed a total of 49 small molecules which may play a role in perturbing the response to EGF of cervical cancer cells. Of these, ciclopirox, etoposide and thioridazine were suggested to have anti-cancer effects in cervical cancer in the published reports. Also, some small molecules were suggested to have an anti-cancer effect in other cancer lines, such as parthenolide and pyrvinium. Further studies are needed to make sure that the use of parthenolide or other anti-cancer agents is effective without inhibiting important host defense mechanisms in cervical cancer.