Inhibition of ABCC9 by zinc oxide nanoparticles induces ferroptosis and inhibits progression, attenuates doxorubicin resistance in breast cancer

Abstract

Background Zinc oxide nanoparticles (ZONs) are a type of nanomaterial that has presented anti-cancer properties in breast cancer (BC). However, the function of ABCC9 in BC and its correlation with ZONs are still elusive. Methods Here, we identified the crucial role of ABCC9 in modulating ferroptosis and doxorubicin (Dox) resistance in BC and the targeted function of ZONs to ABCC9. Results The silencing of ABCC9 significantly repressed the viability of BC cells. The knockdown of ABCC9 decreased the numbers of Edu-positive BC cells. Conversely, BC cell apoptosis was increased by the inhibition of ABCC9. Besides, the silencing of ABCC9 reduced the capability of migration and invasion of BC cells. Significantly, tumorigenicity analysis demonstrated that the tumor growth of BC cells was suppressed by the depletion of ABCC9 in the xenograft model of nude mice. Moreover, the treatment of ferroptosis activator erastin repressed cell viability of BC cells and ABCC9 overexpression rescued the repression. Similarly, the numbers of Edu-positive BC cells were inhibited by erastin and the overexpression of ABCC9 reversed the inhibitory effect of erastin. The levels of GSH were decreased and MDA, lipid ROS, and iron levels were increased by the treatment of erastin, while the ABCC9 overexpression could reverse these results in BC cells. Consistently, erastin suppressed the expression of ferroptosis inhibitory factors, including GPX4 and SLC7A11, in BC cells and the overexpression of ABCC9 rescued the expression. The IC50 value of Dox was reduced by the knockdown of ABCC9 in Dox-resistant BC cells (BC/Dox). The numbers of Edu-positive BC/Dox cells were attenuated by the depletion of ABCC9. Meanwhile, the apoptosis of BC/Dox cells was stimulated by the silencing of ABCC9. Furthermore, the treatment of ZONs attenuated Dox resistance of BC cells. ZONs remarkably repressed the expression of ABCC9 in BC/Dox cells. ZONs inhibited the cell viability of BC/Dox cells and the overexpression of ABCC9 reversed the repression. Moreover, the treatment of ZONs reduced GSH levels and enhanced MDA, lipid ROS, and iron levels in erastin-stimulated BC/Dox cells. Conclusions In conclusion, we discovered that the inhibition of ABCC9 by zinc oxide nanoparticles induces ferroptosis and attenuates Dox resistance in BC.

Ferroptosis resistance in cancer cells: nanoparticles for combination therapy as a solution

“…In cervical cancer, ZONPs not only induce lipid ROS and malondialdehyde (MDA) production but also suppress CD164 by enhancing miR-505-3p levels ( Lei et al, 2022 ). In breast cancer, ZONPs have been shown to counteract resistance to doxorubicin by inhibiting ABCC9 and inducing ferroptosis ( Li Y. et al, 2022 ).…”

Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment

“…Further studies provided strong evidence that restoration of miR-101-3p expression via suitable nanotransfection agents may be a potential candidate therapeutic technique for ferroptosis in various tumors . Previous research has proven zinc oxide nanoparticles (ZONs) are able to induce ferroptosis by targeting p53 in breast cancer, which contributes to the inhibition of ATP-binding cassette (ABC) transporters C9 (ABCC9) that is a regulator of MDR, resulting in attenuation of DOX resistance . It exemplifies that gene interference may induce ferroptosis to reverse drug resistance through nanotechnology.…”

“…282 Previous research has proven zinc oxide nanoparticles (ZONs) are able to induce ferroptosis by targeting p53 in breast cancer, which contributes to the inhibition of ATP-binding cassette (ABC) transporters C9 (ABCC9) that is a regulator of MDR, resulting in attenuation of DOX resistance. 283 It exemplifies that gene interference may induce ferroptosis to reverse drug resistance through nanotechnology. We have summarized some effective genes in overcoming therapeutic resistance through regulating ferroptosis in Table 1.…”