AMP-activated protein kinase: a potential therapeutic target for triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subset of breast carcinomas that lack expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Unlike other breast cancer subtypes, targeted therapy is presently unavailable for patients with TNBC. In spite of initial responses to chemotherapy, drug resistance tends to develop rapidly and the prognosis of metastatic TNBC is poor. Hence, there is an urgent need for novel-targeted treatment methods or development of safe and effective alternatives with recognized mechanism(s) of action. AMP-activated protein kinase (AMPK), an energy sensor, can regulate protein and lipid metabolism responding to alterations in energy supply. In the past 10 years, interest in AMPK has increased widely since it appeared as an attractive targeting molecule for cancer therapy. There has been a deep understanding of the possible role of abnormal AMPK signaling pathways in the regulation of growth and survival and the development of drug resistance in TNBC. The increasing popularity of using AMPK regulators for TNBC-targeted therapy is supported by a considerable development in ascertaining the molecular pathways implicated. This review highlights the available evidence for AMPK-targeted anti-TNBC activity of various agents or treatment strategies, with special attention placed on recent preclinical and clinical advances in the manipulation of AMPK in TNBC. The elaborative analysis of these AMPK-related signaling pathways will have a noteworthy impact on the development of AMPK regulators, resulting in efficacious treatments for this lethal disease.

Keywords: AMP-activated protein kinase; Chemotherapy; Targeted treatment; Triple-negative breast cancer.

Fig. 1

Schematic illustration of the AMPK/mTOR signaling pathway in TNBC tumor growth and progression. mTORC1 comprises mTOR, mammalian lethal with sec-13 protein 8 (mLST8), and regulatory-associated protein of mammalian target of rapamycin (RAPTOR). mTORC1 is activated by growth factors, nutrients (amino acids), and cellular energy. It stimulates anabolic processes, including protein and nucleotide synthesis via ribosomal protein S6 kinase (S6K), eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), and hinders catabolic processes, such as autophagy, through Unc-51-like kinase 1 (ULK1). mTORC2 consists of mTOR, mLST8, mammalian stress-activated map kinase-interacting protein 1 (mSIN1), and rapamycin-insensitive companion of mTOR (RICTOR) and is activated by growth factors. mTORC2 activates the AGC kinase family members Akt, serum/glucocorticoid-regulated kinase (SGK), and protein kinase C (PKC). mTORC1 and mTORC2 are commonly activated in human cancers. AMPK activation inhibits mTORC1; however, the effect on mTORC2/Akt is not completely clear. Moreover, AMPK activation represses expression of EGFR, cyclin D1, and cyclin E and phosphorylation of MAPK, Src, and STAT3

Fig. 2

Proposed molecular action of AMPK activation by various classical/novel AMPK activators in TNBC. Abbreviations: DMC, demethoxycurcumin; AICAR, 5-aminoimidazole-4-carboxamide ribose; SERCA2, sarco/endoplasmic reticulum calcium-ATPase 2; CaMKKβ, Ca2+/calmodulin-dependent kinase kinase-β; RC: respiratory chain; EPHA2, EPH receptor A2; MTDH, metadherin