Andugulapati, SB and Sundararaman, A and Lahiry, M and Rangarajan, A (2022) AMP-activated protein kinase promotes breast cancer stemness and drug resistance. In: DMM Disease Models and Mechanisms, 15 (6).
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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 laboratory demonstrated a context-specific pro-tumorigenic role for AMP-activated protein kinase (AMPK) under anchorage-deprivation and mammosphere formation, which are hallmarks of BCSCs. Therefore, we 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 populations in vivo. AMPK promotes the expression of stemness genes such as NANOG, SOX2 and BMI1 through the transcriptional upregulation of TWIST via promoter acetylation. Further, AMPK-driven stemness plays a critical role in doxorubicin resistance. Significantly, AMPK activity increased after chemotherapy in patient-derived tumour samples alongside an increase in stemness markers. Importantly, AMPK depletion sensitises mouse tumours to doxorubicin treatment. Our work indicates that targeting of AMPK in conjunction with regular chemotherapy is likely to reduce the stem cell pool and improve chemosensitivity in breast cancers. © 2022 Company of Biologists Ltd. All rights reserved.
| Item Type: | Journal Article |
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| Publication: | DMM Disease Models and Mechanisms |
| Publisher: | Company of Biologists Ltd |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | 6,7 dihydro 4 hydroxy 3 (2' hydroxy 1,1' biphenyl 4 yl) 6 oxothieno2,3 bpyridine 5 carbonitrile; ABC transporter; BMI1 protein; breast cancer resistance protein; CD24 antigen; cisplatin; complementary DNA; doxorubicin; doxycycline; fluorouracil; Hermes antigen; histone acetyltransferase; histone H2B; hydroxymethylglutaryl coenzyme A reductase kinase; hydroxymethylglutaryl coenzyme A reductase kinase alpha 2; methotrexate; multidrug resistance associated protein 1; multidrug resistance protein 1; octamer transcription factor 4; transcription factor NANOG; transcription factor Sox2; Twist related protein 1; unclassified drug, animal cell; animal experiment; animal model; Article; breast cancer; BT-474 cell line; cancer chemotherapy; cancer resistance; cancer stem cell; cell population; chemosensitivity; controlled study; female; gene expression; human; human cell; human tissue; in vitro study; in vivo study; MCF-7 cell line; MDA-MB-231 cell line; mouse; multiple cycle treatment; nonhuman; promoter region; protein acetylation; protein depletion; protein expression; real time polymerase chain reaction; single cell analysis; transcription regulation; treatment outcome; upregulation |
| Department/Centre: | Division of Biological Sciences > Molecular Reproduction, Development & Genetics |
| Date Deposited: | 16 Sep 2022 08:35 |
| Last Modified: | 16 Sep 2022 08:35 |
| URI: | https://eprints.iisc.ac.in/id/eprint/76543 |
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