Abstract
Transcription factor AP-1 plays a central role in HPV-mediated cervical carcinogenesis. AP-1 has also been implicated in chemo-radio-resistance but the mechanism(s) remained unexplored. In the present study, cervical cancer stem-like cells (CaCxSLCs) isolated and enriched from cervical cancer cell lines SiHa and C33a demonstrated an elevated AP-1 DNA-binding activity in comparison to non-stem cervical cancer cells. Upon UV-irradiation, CaCxSLCs showed a UV exposure duration-dependent higher proliferation and highly increased AP-1 activity whereas it was completely abolished in non-stem cancer cells. CaCxSLCs also showed differential overexpression of c-Fos and c-Jun at transcript as well as in protein level. The loss of AP-1 activity and expression was accompanied by decrease in cell viability and proliferation in UV-irradiated non-stem cancer cells. Interestingly, CaCxSLCs treated with curcumin prior to UV-irradiation abolished AP-1 activity and a concomitant reduction in SP cells leading to abrogation of sphere forming ability, loss of proliferation, induction of apoptosis and the cells were poorly tumorigenic. The curcumin pre-treatment abolished the expression of c-Fos and c-Jun but upregulated Fra-1 expression in UV-irradiated CaCxSLCs. Thus, the study suggests a critical role of AP-1 protein in the manifestation of radioresistance but targeting with curcumin helps in radiosensitizing CaCxSLCs through upregulation of Fra-1.
Highlights
Cervical cancer is a major reproductive health problem in women of developing countries[1]
The sorted cells were examined for their stemness property by cervicosphere formation assay using intermittent culturing in low adherence defined conditioned medium (DCM)
Cervicospheres were absent in non-side population (NSP) [NSP → (CD49f−veCD71+ve) → CD133−ve] (Fig. 1F) designated as non-CaCxSLCs when they were cultured on comparable media and surface condition as it resulted in anoikis of cells as reported earlier[26]
Summary
Cervical cancer is a major reproductive health problem in women of developing countries[1]. Subsequent studies showed involvement of AP-1 family members in mediating resistance to anti-cancer therapies demonstrated a potential role of c-Jun in chemo-radioresistance www.nature.com/scientificreports/. Increased expression of phosphorylated c-Jun and c-Fos were found essential for induction of apoptosis in response to UV irradiation[21] indicating cell to cell context dependent c-Jun functional variation These studies along with investigations involving inhibition of AP-1 activity[14, 21] reemphasized important role of AP-1 in governing radioresistance but the effect were AP-1 member-specific in different cancers. Recent investigations suggest that AP-1 could play a pivotal role in governing radio- or chemo-resistance of CSCs21, 22 It is not understood how AP-1 which governs oncogenic activity of HPV is involved in manifestation of radioresistance of CSCs in cervical cancer. Curcumin has been shown to act as a radiosensitizer[24, 25] but the mechanism by which curcumin alleviate radioresistance is not clear
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