Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy

Abstract

Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development.

AG311, a small molecule inhibitor of complex I and hypoxia-induced HIF-1α stabilization

“…Reduced complex I activity results in energy stress as characterized by the increase in AMP/ATP ratio and subsequent activation of AMPK, as shown in tumors from AG311-treated mice (Fig 4E). Although this data supports the idea that AG311 inhibits complex I, the activation of AMPK by AG311 also raises the potential for resistance due to AMPK-mediated survival [41,42]. This activation of AMPK requires the upstream kinase LKB1, which has been characterized as a tumor suppressor [43].…”

Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPKα1/2-LKB1

“…A growing body of evidence demonstrates that loss of AMPKα1/2 expression is associated with enhanced tumorigenesis whereas induction of AMPKα1/2 expression is related to reduced cancer cell growth 13, 14 . Activation of AMPKα1/2 has emerged as a novel strategy for prevention and treatment of cancer and several metabolic diseases 13, 14, 47 . Our data demonstrate that cryptolepine reduces ATP production in melanoma cells and enhances both the levels of AMPKα1/2 protein and its phosphorylation.…”

“…Various phytochemicals, including flavonoids, grape polyphenol (resveratrol), green tea polyphenol (EGCG), honokiol, curcumin and berberine, that have demonstrated significant anticancer potential have been shown to target bioenergetics and activation of the metabolic tumor suppressor AMPKα1/2 and other signaling pathways involved in tumor growth and progression 14, 61, 62 . Interestingly, honokiol, a phytochemical derived from Magnolia grandiflora , also showed activity in vemurafenib-resistant melanoma through induction of respiratory enzyme succinate dehydrogenase in in vivo model 63 .…”

“…Expression of Sirtuins (SIRT1 and SIRT3) also is related to enhanced tumorigenesis and metastasis through their regulation of mitochondrial biogenesis and activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) 10, 11 . AMP-activated protein kinase (AMPK), which is a metabolic tumor suppressor, acts as an energy sensor 12, 13 and maintains energy homeostasis as well as regulating various processes associated with tumor development such as cell growth, cell survival, cell cycle progression and apoptosis 13, 14 .…”

Drug repurposing against COVID-19: focus on anticancer agents

“…More recently, CQ has attracted the oncologists for its ability of interfering with the late stages of autophagy, by producing cytoplasmic accumulation of non-functional autophagic vesicles [22]. Both normal and cancer cells utilize autophagy for energetic purposes, but cancer cells, due to their higher energy requirements, rely more actively on autophagy, after being stressed by radio-or chemotherapy [23][24][25]. Therefore, the association of first-line therapeutic approaches in cancer patients with autophagy inhibitors has been largely investigated [26,27] and suggested [26][27][28] and clinically investigated in clinical trials, mainly in CNS tumors [29][30][31].…”