Molecular iodine inhibits the expression of stemness markers on cancer stem-like cells of established cell lines derived from cervical cancer

Gabriele Davide Bigoni-Ordóñez,Heriberto A Valencia-González,Alejandro García-Carrancá,Carmen Aceves,Elizabeth Ortiz-Sánchez,Pedro Rosendo-Chalma

doi:10.1186/s12885-018-4824-5

Abstract

BackgroundCancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors. Targeting CSC will provide novel treatments for cancer. Different investigations have focused on developing complementary approaches that involve natural compounds that decrease chemo-resistance and reduce the side effects of conventional therapies. Since, it has been reported that molecular iodine (I2) exhibits antineoplastic effects and decreases tumor progression in some cancer models, we evaluated the potential effect of I2 on cell cultures enriched in cervical cancer stem-like cells.MethodsHeLa and SiHa cervical cancer cells were treated with 200uM I2 for 24 h. After time, cells were cultured in CSC-conditioned medium (cervospheres) and viability assays were performed. Following, tumorigenic capabilities in cervospheres treated with I2 were evaluated in NOD/SCID mice. HeLa monolayer cells untreated and their respective cervosphere cells treated or untreated with 200 μM of I2 for 24 h were xenotransplanted subcutaneously at different amounts and mice were monitored for at least 2 months.ResultsIn the present study, monolayer and CSC-enriched cultures (cervospheres) from cervical cancer-derived cell lines, HeLa and SiHa, showed that 200uM I2 supplementation inhibits proliferation of both and decreased their tumorigenic capacity, in vivo. This antineoplastic effect of I2 was accompanied by diminished expression of stemness markers including CD49f, CK17, OCT-4, NANOG, SOX2, and KLF4, as well as increased expression and activation of PPARγ receptors.ConclusionsAll this data led us to suggest a clinical potential use of I2 for targeting CSC and improve current treatments against cervical cancer.

Highlights

Cancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors
We found the highest protein level of CD49f suggesting a significant proportion of cancer stem cell-like cells
In this work we show that in cancer stem cells (CCSC)-like cells derived from Molecular Iodine (I2)-treated cervical cancer cell lines, PPAR gamma protein level was increased compared to untreated CCSC-like cells

Summary

Introduction

Cancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors. Cervical cancer is the 4th most common cancer in women with an estimated of 528,000 new cases in 2012 and 266,000 deaths. High-risk human papillomaviruses (HPV) are related for the development of cervical cancer [2]. This is achieved through the persistent infection of HPV until later integrates his viral DNA into the host cell. The E6 function of high-risk HPV types is the binding and targeting of p53 for degradation and the function of E7 is binding the retinoblastoma tumor suppressor protein (pRb) for degradation allowing the release of the transcription factor (EF2) that promotes the expression of numerous genes that control DNA synthesis and cell proliferation [3, 4]

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