Inhibition of RAD51 by siRNA and Resveratrol Sensitizes Cancer Stem Cells Derived from HeLa Cell Cultures to Apoptosis

Abstract

Cervical cancer is the second most frequent tumor type in women worldwide with cases developing clinical recurrence, metastasis, and chemoresistance. The cancer stem cells (CSC) may be implicated in tumor resistance to therapy. RESveratrol (RES), a natural compound, is an antioxidant with multiple beneficial activities. We previously determined that the expression of RAD51 is decreased by RES. The aim of our study was to examine molecular mechanism by which CSC from HeLa cultures exhibit chemoresistance. We hypothesized CSC repair more efficiently DNA breaks and that RAD51 plays an important role in this mechanism. We found that CSC, derived from cervical cancer cell lines, overexpress RAD51 and are less sensitive to Etoposide (VP16). We inhibited RAD51 in CSC-enriched cultures using RES or siRNA against RAD51 messenger RNA and observed a decrease in cell viability and induction of apoptosis when treated simultaneously with VP16. In addition, we found that inhibition of RAD51 expression using RES also sensitizes CSC to VP16 treatment. Our results suggest that resveratrol is effective to sensitize cervical CSC because of RAD51 inhibition, targeting high RAD51 expressing CD49f-positive cells, which supports the possible therapeutic application of RES as a novel agent to treat cancer.

Natural Compounds That Target DNA Repair Pathways and Their Therapeutic Potential to Counteract Cancer Cells

“…Etoposide in combination with resveratrol treatments were more effective than either chemical alone given as treatment to stop cell proliferation and eliminate non-small-cell lung cancer cells by suppressing the expression of the XRCC1 protein (DNA repair protein within NER or BER pathway) (24). The same happened in sphere cultures of cervical cancer cells treated with this combination, but in this case a strong decrease in the expression of the RAD51 protein (DNA repair protein within HR pathway) was reported (25). Resveratrol potentiates the effects of temozolomide on glioblastoma cells by negatively regulating the NF-kB pathway and thereby causing a reduction in MGMT expression (26).…”

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

“…Glioma stem cell↓; Cervical cancer stem cells↓; Breast cancer stem cells↓; Colon cancer stem cells↓; Leukemia stem cell↓…”

miR‐4429 sensitized cervical cancer cells to irradiation by targeting RAD51

“…In the current study, we identified RAD51 as a putative target for miR‐4429 by searching miRDB. RAD51 is known to play a pivotal role in modulating HR to facilitate DNA repair (Bindra et al, ; Ruíz et al, ). The role of RAD51 as a contributor for radio‐resistance and chemoresistance has been reported in many cancers (S. Chen et al, ; Short et al, ), including in CC (Wang et al, ).…”