Autophagy: An emerging target for cancer therapy

Høyer-Hansen, Maria; Jäättelä, Marja

doi:10.4161/auto.5921

Cited by 180 publications

(142 citation statements)

References 82 publications

Supporting

Mentioning

141

Contrasting

Order By: Relevance

“…New strategies to kill cancer cells by nonapoptotic mechanisms have flourished during the past decade, and many mediators of alternate cell death pathways have been identified (3)(4)(5)(6). Among them are the lysosomes with their large arsenal of proteolytic and lipolytic hydrolases (4,34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Defects in apoptosis signaling pathways are, however, among the major hallmarks of cancer, and apoptosis-inducing therapies further select for highly apoptosis refractory tumor cell clones (1,2). Accordingly, new strategies to kill cancer cells by nonapoptotic mechanisms have flourished during the past decade, and many inducers of alternative caspase-independent cell death pathways have been identified (3)(4)(5)(6). Among them is a lipid:protein complex composed of oleic acid and human α-lactalbumin that was originally purified from human milk and termed HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) based on its ability to effectively kill transformed cells while leaving nontransformed cells largely unaffected (7,8).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

Self Cite

119

View full text Add to dashboard Cite

A complex of human α-lactalbumin and oleic acid (HAMLET) was originally isolated from human milk as a potent anticancer agent. It kills a wide range of transformed cells of various origins while leaving nontransformed healthy cells largely unaffected both in vitro and in vivo. Importantly, purified α-lactalbumins from other mammals form complexes with oleic acid that show biological activities similar to that of HAMLET. The mechanism by which these protein-lipid complexes kill tumor cells is, however, largely unknown. Here, we show that complex of bovine α-lactalbumin and oleic acid (BAMLET), the bovine counterpart of HAMLET, kills tumor cells via a mechanism involving lysosomal membrane permeabilization. BAMLET shows potent cytotoxic activity against eight cancer cell lines tested, whereas nontransformed NIH-3T3 murine embryonic fibroblasts are relatively resistant. BAMLET accumulates rapidly and specifically in the endolysosomal compartment of tumor cells and induces an early leakage of lysosomal cathepsins into the cytosol followed by the activation of the proapoptotic protein Bax. Ectopic expression of three proteins known to stabilize the lysosomal compartment, i.e. heat shock protein 70 (Hsp70), Hsp70-2, and lens epithelium-derived growth factor, confer significant protection against BAMLET-induced cell death, whereas the antiapoptotic protein Bcl-2, caspase inhibition, and autophagy inhibition fail to do so. These data indicate that BAMLET triggers lysosomal cell death pathway in cancer cells, thereby clarifying the ability of α-lactalbumin:oleate complexes to kill highly apoptosis-resistant tumor cells. Mol Cancer Ther; 9(1); 24-32. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

Self Cite

119

View full text Add to dashboard Cite

show abstract

“…On one hand, it can serve as a cytoprotective mechanism, allowing tumor cells to survive under conditions of metabolic stress and hypoxia and to escape anticancer treatment-induced cell death. On the other hand, autophagy induced by therapeutic interventions can cause the death of cancer cells that are resistant to apoptosis (54,55). Certain anticancer agents, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor xenograft Model-The experiments conformed to the Animal Management Rule of the Chinese Ministry of Health (documentation 55,2001), and the experimental protocol was approved by the Animal Care and Use Committee of Shandong University. BALB/c nude (nu/nu) female mice were purchased from Vital River Laboratories.…”

Section: Methodsmentioning

confidence: 99%

Cucurbitacin I Induces Protective Autophagy in Glioblastoma in Vitro and in Vivo

Yuan

Yan

Xue

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Targeting disruption of STAT3 results in inhibition of tumor growth and survival in malignant glioma. Results: Cucurbitacin I triggers protective autophagy through the AMPK/mTOR/p70S6K pathway and down-regulates HIF-1␣. Conclusion: Autophagy blockade sensitizes glioblastoma to cucurbitacin I treatment. Significance: This study provides new insights into the biological and antiproliferative activities of cucurbitacin I against glioblastoma.

show abstract

“…Whereas autophagy clearly has a beneficial effect in preventing many degenerative disorders, its role in cancer is more complex. It can function as a tumor suppressor mechanism, and yet it can also promote tumor growth by protecting cancer cells against the hostile tumor environment and antineoplastic drugs (5,6).…”

mentioning

confidence: 99%

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Farkas

Daugaard

Jäättelä

2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Macroautophagy (hereafter autophagy) is a lysosomal catabolic pathway that controls cellular homeostasis and survival. It has recently emerged as an attractive target for the treatment of a variety of degenerative diseases and cancer. The targeting of autophagy has, however, been hampered by the lack of specific small molecule inhibitors. Thus, we screened two small molecule kinase inhibitor libraries for inhibitors of rapamycin-induced autophagic flux. The three most potent inhibitors identified conferred profound inhibition of autophagic flux by inhibiting the formation of autophagosomes. Notably, the autophagy inhibitory effects of all three compounds were independent of their established kinase targets, i.e. ataxia telangiectasia mutated for KU55933, protein kinase C for Gö6976, and Janus kinase 3 for Jak3 inhibitor VI. Instead, we identified phosphatidylinositol 3-kinase (PtdIns3K) as a direct target of KU55933 and Gö6976. Importantly, and in contrast to the currently available inhibitors of autophagosome formation (e.g. 3-methyladenine), none of the three compounds inhibited the cell survival promoting class I phosphoinositide 3-kinase-Akt signaling at the concentrations required for effective autophagy inhibition. Accordingly, they proved to be valuable tools for investigations of autophagy-associated cell death and survival. Employing KU55399, we demonstrated that autophagy protects amino acid-starved cells against both apoptosis and necroptosis. Taken together, our data introduce new possibilities for the experimental study of autophagy and can form a basis for the development of clinically relevant autophagy inhibitors.Autophagy is an intracellular degradative process by which cells recycle macromolecules and organelles (1-4). In this process, cellular material is sequestered in double membrane vesicles termed autophagosomes that fuse with lysosomes to form autolysosomes, in which the cargo is exposed to acidic hydrolases. Autophagy is essential for energy homeostasis and removal of damaged organelles and protein complexes during various kinds of stresses, such as starvation, growth factor deprivation, hypoxia, and DNA damage. It is also involved in physiological processes like development, immunity, and aging as well as in various diseases including neurodegenerative disorders and cancer. Whereas autophagy clearly has a beneficial effect in preventing many degenerative disorders, its role in cancer is more complex. It can function as a tumor suppressor mechanism, and yet it can also promote tumor growth by protecting cancer cells against the hostile tumor environment and antineoplastic drugs (5, 6).The mammalian target of rapamycin complex 1 (mTORC1) 3 serine/threonine kinase integrates information on cell metabolic, growth, and stress status to regulate biosynthetic pathways and autophagy (7,8). It activates biosynthetic pathways and inhibits autophagy in response to various growth factors via MAPK/ERK and class I phosphoinositide 3-kinase (PI3K)/Aktdependent pathways. On the other hand, when the ene...

show abstract

Autophagy: An emerging target for cancer therapy

Cited by 180 publications

References 82 publications

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Cucurbitacin I Induces Protective Autophagy in Glioblastoma in Vitro and in Vivo

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Contact Info

Product

Resources

About