Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

Abstract

The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers.

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

“…Therefore, it was hypothesized that ATP levels may be lower in p53 -/cells due to uncontrolled rapid cell proliferation and growth, which may cause much higher consumption of ATP. ATP depletion is the main signal that induces AMPK activation by phosphorylation of Thr172 (44)(45)(46). The present study demonstrated that serum starvation markedly increased phosphorylation of AMPK at Thr172 in HCT116 p53 -/cells compared with in HCT116 p53 +/+ cells.…”

p53 Promotes chemoresponsiveness by regulating hexokinase II gene transcription and metabolic reprogramming in epithelial ovarian cancer

“…This leads to a change in the ATP‐to‐AMP ratio and canonical AMPK activation. It inhibits cell growth through suppressing mTOR signaling . In this context, it is possible that metformin inhibits HKII‐PDK1 loop via suppressing AMPK/mTOR .…”

“…It inhibits cell growth through suppressing mTOR signaling. 44,45 In this context, it is possible that metformin inhibits HKII-PDK1 loop via suppressing AMPK/mTOR. 46 Additional studies are needed to determine whether the role of metabolism in chemoresistance in OVCA is histologic subtypedependent.…”

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

“…The AMP-activated protein kinase (AMPK), a cellular metabolic sensor, participates in maintaining energy homeostasis under external stresses in multiple human cancers. 129 The AMPK, expressed extensively in all eukaryotic cells, comprises of a catalytic subunit (α) and two regulatory subunits (β and γ). 130 , 132 According to different inputs, outputs, functions, and sub-cellular localizations, a total of 12 potential AMPK complexes were assembled by various isoforms of each subunit.…”