Cytoprotective Effect of the Elongation Factor-2 Kinase-Mediated Autophagy in Breast Cancer Cells Subjected to Growth Factor Inhibition

Cheng, Yan; Huai-jun, LI; Ren, Xingcong; Niu, Ting-Kuang; Hait, William N.; Yang, Jin‐Ming

doi:10.1371/journal.pone.0009715

Cited by 77 publications

(67 citation statements)

References 38 publications

(41 reference statements)

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“…It has been reported previously (Araki and Motojima, 2008) that statins do not induce autophagy in HepG2 cells. These results are not due to a lack of inducible autophagy, as both HepG2 and MDA-MB-468 have been reported to be capable of autophagic induction (Cheng et al, 2010;Wang et al, 2010).…”

Section: Discussionmentioning

confidence: 71%

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

Wasko¹,

Dudakovic²,

Hohl³

2011

J Pharmacol Exp Ther

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Multiple studies have implicated the depletion of isoprenoid biosynthetic pathway intermediates in the induction of autophagy. However, the exact mechanism by which isoprenoid biosynthesis inhibitors induce autophagy has not been well established. We hypothesized that inhibition of farnesyl diphosphate synthase (FDPS) and geranylgeranyl diphosphate synthase (GGDPS) by bisphosphonates would induce autophagy by depleting cellular geranylgeranyl diphosphate (GGPP) and impairing protein geranylgeranylation. Herein, we show that an inhibitor of FDPS (zoledronate) and an inhibitor of GGDPS (digeranyl bisphosphonate, DGBP) induce autophagy in PC3 prostate cancer and MDA-MB-231 breast cancer cells as measured by accumulation of the autophagic marker LC3-II. Treatment of cells with lysosomal protease inhibitors [(2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester (E-64d) and pepstatin A] in combination with zoledronate or digeranyl bisphosphonate further enhances the formation of LC3-II, indicating that these compounds induce autophagic flux. It is noteworthy that the addition of exogenous GGPP prevented the accumulation of LC3-II and impairment of Rab6 (a GGTase II substrate) geranylgeranylation by isoprenoid pathway inhibitors (lovastatin, zoledronate, and DGBP). However, exogenous GGPP did not restore isoprenoid pathway inhibitorinduced impairment of Rap1a (a GGTase I substrate) geranylgeranylation. In addition, specific inhibitors of farnesyl transferase and geranylgeranyl transferase I are unable to induce autophagy in our system. Furthermore, the addition of bafilomycin A1 (an inhibitor of autophagy processing) enhanced the antiproliferative effects of digeranyl bisphosphonate. These results are the first to demonstrate that bisphosphonates induce autophagy. Our study suggests that induction of autophagy in PC3 cells with these agents is probably dependent upon impairment of geranylgeranylation of GGTase II substrates.

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Section: Discussionmentioning

confidence: 71%

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

Wasko¹,

Dudakovic²,

Hohl³

2011

J Pharmacol Exp Ther

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“…eEF-2K expression (mRNA) correlates poorly with outcome for at least three types of cancer, including hormone-sensitive breast cancer and glioblastoma (10 -17), and has been shown to promote the survival of various cancer cell lines in response to a range of stresses (13,14,(17)(18)(19)(20). Most notably, it has been shown to mediate an adaptive response to severe nutrient deprivation in transformed cells, suggesting that it confers protection to the hypoxic and nutrient-deprived environment of the tumor (17).…”

Section: Eef-2kmentioning

confidence: 99%

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

Tavares¹,

Ferguson

Giles

et al. 2014

Journal of Biological Chemistry

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Background: Eukaryotic elongation factor 2 kinase (eEF-2K) regulates protein translation elongation rates. Results: eEF-2K activation involves a two-step process of calmodulin binding and rapid Thr-348 autophosphorylation. Conclusion: Activation of eEF-2K involves two distinct allosteric steps, both of which potentially induce a conformational change. Significance: This mechanism provides a framework for understanding how eEF-2K integrates inputs from multiple upstream signaling pathways.

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“…261,262 Autophagy inhibition can be used in combination with other drugs, for instance, to enhance the effectiveness of growth factor inhibitors used to treat cancer. 263 An advantage of targeting autophagy in tumors is that autophagy inhibitors that affect lysosomal pH have already been shown to be safe and effective in people based on their use as antimalarials and as treatment for autoimmune disease.…”

Section: Quiescence In Dormant Cancer Cellsmentioning

confidence: 99%

Staying alive

et al. 2012

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Ensuring the continuity of life requires that individual cells and entire organisms can survive not only in ideal environments, but also in conditions of scarcity. When conditions are unfavorable for proliferation, many cells have the capacity to enter a nondividing state, sometimes for years, while retaining their ability to reenter the proliferative cell cycle. 1,2 This state of reversible cell cycle arrest, known as quiescence, is common and can be seen in stem cells, eggs and spores. Some quiescent cells are surprisingly hardy: they can survive long periods of nutrient starvation, cold temperatures and even desiccation. Entry into quiescence is often associated with dramatic changes in metabolism, defined as the uptake of nutrients and the use of these nutrients for the synthesis of macromolecules and energy. Indeed, proliferating and quiescent fibroblasts are expected to have very different metabolic requirements. While proliferating cells must devote much of their metabolic capacity to biosynthesis in order to create the material necessary to form a new cell, quiescent cells are relieved of this steep metabolic requirement. Many but not all quiescent cells respond by downregulating the synthesis of proteins *Correspondence to: Hilary Coller; Email: hcoller@princeton.edu Submitted: 02/22/12; Accepted: 02/27/12 http://dx.doi.org/10. 4161/cc.19879 Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. in some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the Pi3Kinase/TOr signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOr kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. in this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems. 2 The signals for quiescence vary for different types of cells. Bacteria and yeast can enter stationary phase, a condition in which they cease cell growth and proliferation, in response to depletion of the glucose in their culture medium or in response to deprivation for a specific nutrient. In mammals, the proliferative state of individual cells is regulated by a host of factors that include not only the presence or absence of nutrients, but also cues from proliferative signaling molecules such as mitogens and situational cues. Quiescent T lymphocytes respond to stimulation of their T-cell receptor with the approp...

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Cytoprotective Effect of the Elongation Factor-2 Kinase-Mediated Autophagy in Breast Cancer Cells Subjected to Growth Factor Inhibition

Cited by 77 publications

References 38 publications

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

Bisphosphonates Induce Autophagy by Depleting Geranylgeranyl Diphosphate

The Molecular Mechanism of Eukaryotic Elongation Factor 2 Kinase Activation

Staying alive

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