AMP-activated protein kinase promotes breast cancer stemness and drug resistance

Abstract

Breast Cancer Stem Cells (BCSCs) are a major cause of therapy resistance and tumour progression. Currently, their regulation is not entirely understood. Previous work from our lab demonstrated context-specific pro-tumorigenic role of AMP-activated protein kinase (AMPK) in breast cancer cell survival under anchorage-deprivation and mammosphere formation hallmarks of BCSCs. We therefore investigated the role of AMPK in the maintenance of BCSC state/function. AMPK depletion reduces serial sphere formation in vitro and tumour initiation in vivo. Intriguingly, tumour-derived cell analysis using stem cell markers and functional assays revealed that AMPK is required for the maintenance of BCSC population in vivo. AMPK promotes the expression of stemness genes like Nanog, Sox2 and Bmi1 through the transcriptional upregulation of Twist via promoter acetylation. Further, AMPK-driven stemness plays a critical role in resistance to doxorubicin. Significantly, we found that AMPK activity increased after chemotherapy in patient-derived tumour samples alongside an increase in stemness markers. Importantly, AMPK depletion sensitises mice tumours to doxorubicin treatment. Our work indicates that targeting AMPK in conjunction with regular chemotherapy is likely to reduce the stem cell pool and improve chemosensitivity in breast cancers.

Selenium Yeast and Fish Oil Combination Diminishes Cancer Stem Cell Traits and Reverses Cisplatin Resistance in A549 Sphere Cells

“…Recent studies supported the notion that AMPK activation enhances the anticancer effects of cisplatin [ 62 , 63 ]. Nevertheless, some studies reported conflicting results on the tumor-promoting effects of AMPK activation [ 64 , 65 ]. Now, it is proposed that AMPK can behave as a CSC “friend” or “foe” in a tissue type-specific and context-dependent manner [ 65 ].…”

“…Nevertheless, some studies reported conflicting results on the tumor-promoting effects of AMPK activation [ 64 , 65 ]. Now, it is proposed that AMPK can behave as a CSC “friend” or “foe” in a tissue type-specific and context-dependent manner [ 65 ]. The widespread use of AMPK activators should be trialed cautiously across disease settings of cancers [ 64 ].…”

Design and synthesis of Meldrum's acid based 7-azaindole anchored 1,2,3-triazole hybrids as anticancer agents

“…After 48 h of incubation, cells were subjected to RNA isolation as described earlier. 54 Briefly, 0.5 mL of Trizol (Sigma Aldrich) was added to the cells and then 0.2 mL of chloroform was added and centrifuged gently for the aqueous layer separation. Further, the aqueous layer was separated into the fresh tube and an equal volume of isopropanol was added to precipitate the RNA.…”

Synthesis and Characterization of a New Cationic Lipid: Efficient siRNA Delivery and Anticancer Activity of Survivin‐siRNA Lipoplexes for the Treatment of Lung and Breast Cancers**

“…After, 12 h of seeding cells were treated with lipoplexes namely; ED, EC, MC, and MD, liposomes; EDL, ECL, MCL, and MDL and PBS for 24 h. After 24 h of treatment, cells were trypsinized and resuspended in a 500 μL binding buffer containing annexin‐V FITC/PI and incubated for 15 min in the dark. Then the samples were analyzed using a flow cytometer (FACS accuri, Beckton Dickinson, USA) and apoptosis was analyzed using BD‐Accuri software [48,50] …”