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| Home > Publications database > Rac1 inhibition promotes antitumor activity of statins in bone-seeking breast cancer cells. |
| Home > Publications database > Rac1 inhibition promotes antitumor activity of statins in bone-seeking breast cancer cells. |
| Journal Article | DKFZ-2025-02557 |
; ; ;
2025
Elsevier B.V.
[Amsterdam]
Abstract: Bone metastases are the most common site of cancer spread in breast cancer (BC) and are associated with a poor prognosis. Statins elicit antitumor activity in vitro, but supraphysiological doses are often required to achieve these effects. Inhibition of the mevalonate pathway by statins prevents the prenylation of small Rho-GTPases including Rac1. Therapeutic approaches to increase statin sensitivity of tumor cells remain scarce. We investigated whether the combined inhibition of the mevalonate pathway and Rac1 potentiates antitumor effects in osteotropic triple-negative BC (TNBC) cells.MDA-MET, MDA-BONE, and MDA-MB-231 TNBC cells were exposed to statins and either pharmacological Rac1 inhibitors or Rac1 knockdown via siRNAs. Antitumor effects were quantified by viability and apoptosis analysis, Western blot analyses, and gene expression of tumor-related mediators.The combined inhibition of the mevalonate pathway by statins and Rac1 via siRNAs induced significant additive antitumor effects in TNBC cell lines. Required concentrations of statins to induce apoptosis and to reduce vitality could be reduced when cells were genetically depleted of Rac1. Triple knockdown of Rac1, RhoA, and CDC42 partially prevented the potentiated antitumor effects by the statin and Rac1-specific siRNA combination.Genetic inhibition of Rac1 sensitizes osteotropic TNBC cell lines to statin treatment. Our results support a pro-tumorigenic function of Rac1 and indicate a potential benefit of combining Rac1 inhibition with statin treatment in osteotropic TNBC.
Keyword(s): Antitumor effect ; Mevalonate pathway ; Osteotropic breast cancer ; Rac1 ; Statins
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