Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Abstract

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

AKT2 drives cancer progression and is negatively modulated by miR-124 in human lung adenocarcinoma

“…Among these three, AKT2 is much more closely associated with cancer cell metabolism, proliferation, cell survival, metastasis, angiogenesis and drug resistance [6]. In breast cancer, inhibition of AKT2 can not only effectively prevent the transformation of mesenchymal non-cancer stem cells (non-CSC) into epithelial cells but also reduce the invasive and colony formation abilities of non-CSC and CSC [7]. In colon cancer, the expression of AKT2 can affect the DNA repair ability and radiosensitivity [8].…”

Ultrasound Microbubbles-mediated Microrna-505 Regulates Cervical Cancer Cell Growth via AKT2

“…Knockdown of AKT2 prevented cell proliferation and stimulated apoptosis in CC cells [43]. A recent study showed that AKT2 inhibition is potential for anti-cancer therapies for its function in EMT reversion, metastasis reduction and tumor recurrence prevention [44]. To sum up, AKT2 silencing is possible to prevent CC development.…”

Ultrasound Microbubble-Mediated microRNA-505 Regulates Cervical Cancer Cell Growth via AKT2

“…The knockdown of AKT2 prevented cell proliferation and stimulated apoptosis in CC cells [ 45 ]. A recent study showed that AKT2 inhibition has the potential for anticancer therapies for its function in EMT reversion, metastasis reduction, and tumor recurrence prevention in breast cancer [ 46 ]. To sum up, AKT2 silencing is possible to prevent CC development.…”