Therapeutic starvation and autophagy in prostate cancer: A new paradigm for targeting metabolism in cancer therapy

DiPaola, Robert S.; Dvorzhinski, Dmitri; Thalasila, Anu; Garikapaty, V.; Doram, Donyell; May, Michael; Bray, Kevin; Mathew, Robin; Beaudoin, Brian; Karp, Cristina M.; Stein, Mark N.; Foran, David J.; White, Eileen

doi:10.1002/pros.20837

Cited by 93 publications

(88 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interaction of hexokinase II and Akt/mTOR pathway DJ Roberts and S Miyamoto with 5-25 mM commonly used [164][165][166] ) inhibited autophagy development in the absence of glucose in cardiomyocytes. This observation implied that HK-II acts to stimulate autophagy in the absence of its substrate.…”

Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

View full text Add to dashboard Cite

Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

show abstract

Section: Hk-ii-mediated Regulation Of Mtorc1 and Autophagymentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

View full text Add to dashboard Cite

show abstract

“…Additionally, high grade (Gleason > 7) and castration-resistant tumors seem to reactivate glycolysis, since FDG-PET and FDG-PET/CT studies indicate an increased glucose uptake compared to benign and low stage prostate cancers [153][154][155][156][157]. Accordingly, prostate cancer is affected by 2-deoxyglucose [158][159][160]. This is further in agreement with cell line studies, which show that the metastastic androgen-sensitive cell line LNCaP and the castration-resistant low-differentiation cell lines DU-145 and PC-3 are sensitive to glucose starvation [152] and that androgen signaling enhances the expression of glycolytic enzymes [161][162][163].…”

Section: Later Stage Prostate Cancer Metabolismmentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

100

104

View full text Add to dashboard Cite

KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

show abstract

“…Most reports about the role of autophagy in response to nutrient deprivation have focused on cells subjected to complete starvation: depletion of amino acids, serum, glucose and vitamins. However, autophagy is thought to be activated in response to lack of glucose, and it has been shown to be induced and required for survival of prostate cells after treatment with the antiglycolytic 2-DG (DiPaola et al, 2008). Moreover, when apoptosisdeficient cells are subjected to glucose deprivation under hypoxia, autophagy becomes essential to maintain cell survival (Degenhardt et al, 2006).…”

Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

View full text Add to dashboard Cite

Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

show abstract

Therapeutic starvation and autophagy in prostate cancer: A new paradigm for targeting metabolism in cancer therapy

Cited by 93 publications

References 17 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Sugar-free approaches to cancer cell killing

Contact Info

Product

Resources

About