Chemotherapy resistance is a common phenomenon during conventional treatment (platinum-based chemotherapy) of advanced or recurrent cervical cancer. Here, researchers investigated the effects of tanshinone I on cervical cancer cell proliferation and chemotherapy resistance, as well as its potential mechanisms. Western blot analysis showed that tanshinone I significantly inhibited KRAS expression and suppressed AKT phosphorylation. rVista analysis and luciferase reporter gene assays indicated that ELK1 can directly bind to the KRAS promoter and positively regulate KRAS expression. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that overexpression of KRAS or ELK1 significantly attenuated the inhibitory effect of tanshinone I on HeLa cell proliferation. Furthermore, tanshinone I restored cisplatin sensitivity in HeLa CR cells, while overexpression of KRAS or ELK1 significantly inhibited this effect. These findings suggest that tanshinone I exerts its anti-cancer effects on cervical cancer cells by inhibiting ELK1 and downregulating the KRAS-AKT pathway, thereby suppressing cervical cancer cell proliferation and cisplatin resistance.
Here, researchers constructed a KRAS-overexpressing HeLa cell line (Figure 1A). Figures 1B and 1C show that tanshinone I inhibited the viability of HeLa cells in a time-dependent manner compared to the control group. However, the viability of KRAS- or ELK1-overexpressing HeLa cells was significantly increased compared to the tanshinone I group (Figures 1B and 1C). On the other hand, Figures 5D and 5E show that treatment with 4 μM cisplatin for 5 days had little effect on the viability of cells transfected with empty vector, KRAS-overexpressing HeLa CR cells, or ELK1-overexpressing HeLa CR cells compared to the control group. However, combined treatment with cisplatin and tanshinone I inhibited the viability of HeLa CR cells transfected with empty vector (Figures 1D and 1E). Compared to the vector group, transfection with KRAS or ELK1 overexpression plasmids significantly abolished the inhibitory effect of combined cisplatin and tanshinone I treatment on HeLa CR cell viability (Figures 1D and 1E).
Figure 1. KRAS and ELK1 are the functional downstream effectors of tanshinone I. (Dun S, Gao L., 2019)