Open AccessAMP-activated protein kinase promotes breast cancer stemness and drug resistance
Author(s) -
Sai Balaji Andugulapati,
Ananthalakshmy Sundararaman,
Mohini Lahiry,
Annapoorni Rangarajan
Publication year - 2022
Publication title -
disease models and mechanisms
Language(s) - English
Resource type - Journals
eISSN - 1754-8411
pISSN - 1754-8403
DOI - 10.1242/dmm.049203
Subject(s) - ampk , sox2 , homeobox protein nanog , cancer research , stem cell , cancer stem cell , stem cell marker , biology , doxorubicin , bmi1 , protein kinase a , breast cancer , microbiology and biotechnology , cancer , kinase , chemotherapy , transcription factor , embryonic stem cell , gene , biochemistry , genetics , induced pluripotent stem cell
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.