Targeting mitochondrial dynamics by AZD5363 in triple-negative breast cancer MDA-MB-231 cell–derived spheres

Abstract

Breast cancer stem cells (BCSCs) have been suggested to contribute to chemotherapeutic resistance and disease relapse in breast cancer. Thus, BCSCs represent a promising target in developing novel breast cancer treatment strategies. Mitochondrial dynamics in BCSCs were recently highlighted as an available approach for targeting BCSCs. In this study, a three-dimensional (3D) cultured breast cancer stem cell spheres model was constructed. Mitochondrial dynamics and functions were analyzed by flow cytometry and confocal microscopy. We have demonstrated that the protein levels of FIS 1 and Mitofusin 1 were significantly increased in BCSCs. Moreover, Capivasertib (AZD5363) administration could suppress Mitofusin1 expression in BCSCs. Our use of MitoTracker Orange and annexin V double-staining assay suggested that AZD5363 could induce apoptosis in BCSCs. The sensitivity of stem cell spheres to doxorubicin was investigated by CCK8 assay, and our results indicated that AZD5363 could re-sensitize BCSCs to Doxo. Flow cytometry analysis identified doxo-induced CD44 and CD133 expression in BCSCs could be suppressed by AZD5363. In combination with AZD536, doxo-induced apoptosis in the BCSCs was significantly increased. In conclusion, our study explored, for the first time, that AZD5363 could target mitochondrial dynamics in 3D cultured stem cell spheres (BCSCs) by regulating Mitofusin.

Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment

“…For instance, chemotherapy resistance and recurrence in breast cancer is predominantly governed by breast cancer stem cells (BCSCs) [ 18 , 53 ]. Recently, it was demonstrated that BCSCs show significantly elevated levels of fission mitochondrial 1 (Fis1) and MFN1 proteins [54] . Treatment with AZD5363 (Capivasertib) was found to influence mitochondrial dynamics in BCSCs by suppressing MFN1 expression, thereby increasing chemotherapeutic sensitivity of BCSCs to doxorubicin [54] .…”

“…Recently, it was demonstrated that BCSCs show significantly elevated levels of fission mitochondrial 1 (Fis1) and MFN1 proteins [54] . Treatment with AZD5363 (Capivasertib) was found to influence mitochondrial dynamics in BCSCs by suppressing MFN1 expression, thereby increasing chemotherapeutic sensitivity of BCSCs to doxorubicin [54] . Additionally, breast carcinoma cells have been observed to metastasize to organs with a more favorable microenvironment.…”

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions

“…Moreover, two Ellipticine analogues, namely Drpitor1 and Drpitor1a, displayed a selective inhibitory activity against Drp1, which impaired mitochondrial fission; this resulted in the inhibition of cancer cell proliferation and apoptosis in both cancer cell cultures and xenograft mouse models [ 96 ]. In breast cancer stem cells, an increased expression of Mitofusin1 was found and the administration of AZD5363 suppressed Mitofusin1 expression and induced apoptosis [ 97 ].…”