Hope for melatonin to inhibit metastasis of cancer stem cells in ovarian cancer

by Holly Daugherty

Ovarian cancer is a common gynaecological malignancy, ranking fifth in cancer deaths among women. Tumour recurrence is seen in majority of the patients, despite surgery and chemotherapy, due to the stem cell properties of the tumorigenic cells. These cancer stem cells have slow cell cycles, they are capable of self-renewing, they have clonogenicity capacity and can differentiate for tumour development. Cancer stem cells (CSC) create major challenges for treating cancer as they are resistant to chemotherapy and their existence contributes to tumour initiation, metastasis and recurrence creating poor prognosis. Therefore, targeting these CSCs could potentially be a promising treatment for ovarian cancer therapy.

Melatonin is a physiological hormone that regulates sleep, circadian rhythms and affects the immune system. Recently, melatonin has been found to prompt apoptosis in cancer cells and inhibit tumour angiogenesis and metastasis in many cancers including ovarian. The hormone’s surface receptors, MT1 and MT2, can inhibit the production of cAMP as well as the MAPK cascade once activated. This also induces detoxification as it has antioxidant and radical scavenging properties.

In this study, the researchers investigated the anti-tumour effects and role of melatonin in cancer stem cells and the ovarian cancer cells from which they originate by comparing migration and invasiveness.

CSCs were isolated from SKOV3 ovarian cancers based on the expression of the markers CD133 and CD44 using flow cytometry and magnetic-activated cell sorting analysis. Double positive cells were analysed for SOX2 protein expression by real-time PCR, as well as their ability to form spheroids by spheroid formation assay, to confirm the stemness and self-renewal properties. The researchers then performed an MTT assay to evaluate the proliferation and viability of CSCs once incubated with melatonin, and further assessed this with the expression of Ki67. To determine how melatonin effects the invasiveness of CSCs, MMP-2 and MMP-9 levels were evaluated with zymography analysis and RT-PCR. To better understand how melatonin impacts invasion, the expression of the key genes within the EMT process (snail, ZEB1, ZEB2) were analysed. Finally, the transwell migration assay and subsequent incubation with inhibitors was performed to determine the effect melatonin has on CSC migration and to identify which signalling pathway was inhibited.

The researchers demonstrated that melatonin reduces stemness and proliferation of ovarian cancer stem cells, in addition to downregulating the genes involved in the EMT process which plays a role in metastasis. Melatonin displayed significant anti-migratory effects on CSCs, and could potentially be used to treat ovarian cancer patients that have high melatonin receptor levels. Melatonin can also be considered as an adjuvant treatment in combination with chemotherapy in order to inhibit metastasis and tumour invasion.

References

Akbarzadeh, M., Movassaghpour, A., Ghanbari, H., Kheirandish, M., Fathi Maroufi, N., Rahbarghazi, R., Nouri, M. and Samadi, N., 2017. The potential therapeutic effect of melatonin on human ovarian cancer by inhibition of invasion and migration of cancer stem cells. Scientific Reports, 7(1), pp.1-9.

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