Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma

Fan, Qi; Cheng, Christine; Hackett, C. A.; Feldman, Morri; Houseman, Benjamin T.; Nicolaides, Theodore; Haas‐Kogan, Daphne A.; James, C. David; Oakes, Scott A.; Debnath, Jayanta; Shokat, Kevan M.; Weiss, William A.

doi:10.1126/scisignal.2001017

Cited by 253 publications

(250 citation statements)

References 72 publications

Supporting

Mentioning

228

Contrasting

Order By: Relevance

“…27 PI103 has also been shown to induce autophagy of therapy resistant glioma cells and to synergize with various chemotherapeutic drugs to trigger apoptosis of neuroblastoma cells. 14,28 Despite the different growth inhibitory actions of OSU03012 and PI103, both compounds impaired the protein expression of cyclin D1 and Mycn in neuroblastoma cells and MYCN-amplified neuroblastoma cells were more sensitive to OSU03012 or PI103 compared with nonamplified cells (Fig. 1, Table 1).…”

Section: Discussionmentioning

confidence: 99%

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small-molecule inhibitors of phosphoinositidedependent protein kinase-1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo. Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro. In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase-3b (GSK3b) and p70 S6 kinase-1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high-risk MYCN-amplified neuroblastoma.Neuroblastomas are peripheral nervous system tumors that originate in the neural crest and are most commonly found in the adrenal medulla or along the sympathetic chain. 1 These tumors show heterogeneous biological and clinical features, in which a subset is prone to regress through spontaneous apoptosis with little or no therapy while another subset differentiates over time to benign ganglioneuromas. However, the majority of neuroblastomas are malignant with metastatic spread that is difficult to cure with current treatment modalities.2 Amplification of the MYCN gene, which occurs in 40-50% of the high-risk neuroblastoma cases, remains the major key predictor of poor outcome and is associated with advanced-stage disease, rapid tumor progression and low survival.3 Advanced-stage tumors and those with MYCN gene amplification typically show emergence of treatment resistance and new treatment alternatives for these patients are highly warranted.Abnormal activation of the PI3K/Akt signaling pathway is a common event in human cancers and has been validated through epidemiological and experimental studies as being essential for several human tumors, including neuroblastoma.4-6 PI3K is a family of lipid kinases, heterodimeric proteins composed of one catalytic and one regulatory subunit. In the class IA PI3Ks, there are currently three isoforms of the catalytic (p110a, b, and d) and five of the regulatory (p50a, p55a, p85a, p85b, and p55c) subunits, where p50a and p55a are splice variants of p85a. PI3Ks functions as signal transducers downstream of cell-surface receptors, such as receptor tyrosine kinases. Activated PI3Ks phosphorylate the lipid phosphatidyl-inositol 4,5-biphosphate (PIP2) to generate phosphatidyl-...

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Bound antibodies were detected with HRP-linked anti-mouse or anti-rabbit IgG (Calbiochem), followed by ECL (Amersham). Cells positive for cleaved caspase 3 were detected as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

Cheng

Gustafson

Charron

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Malignant glioma, the most common primary brain tumor, is generally incurable. Although phosphatidylinositol-3-kinase (PI3K) signaling features prominently in glioma, inhibitors generally block proliferation rather than induce apoptosis. Starting with an inhibitor of both lipid and protein kinases that induced prominent apoptosis and that failed early clinical development because of its broad target profile and overall toxicity, we identified protein kinase targets, the blockade of which showed selective synthetic lethality when combined with PI3K inhibitors. Prioritizing protein kinase targets for which there are clinical inhibitors, we demonstrate that cyclin-dependent kinase (CDK)1/2 inhibitors, siRNAs against CDK1/2, and the clinical CDK1/2 inhibitor roscovitine all cooperated with the PI3K inhibitor PIK-90, blocking the antiapoptotic protein Survivin and driving cell death. In addition, overexpression of CDKs partially blocked some of the apoptosis caused by PIK-75. Roscovitine and PIK-90, in combination, were well tolerated in vivo and acted in a synthetic-lethal manner to induce apoptosis in human glioblastoma xenografts. We also tested clinical Akt and CDK inhibitors, demonstrating induction of apoptosis in vitro and providing a preclinical rationale to test this combination therapy in patients.

show abstract

“…CQ Enhances Antiproliferative Activity of OSU-53-Although autophagy can mediate either protective or destructive cellular response to metabolic stress or therapeutic agents (50), evidence indicates that autophagy acts as a survival signal in response to inhibitors of the PI3K-Akt-mTOR signaling axis (51). In this context, we examined the effect of CQ, a lysosomotropic inhibitor of autophagy, on antiproliferative activity in vitro of the OSU-53.…”

Section: Il-6mentioning

confidence: 99%

Targeting Energy Metabolic and Oncogenic Signaling Pathways in Triple-negative Breast Cancer by a Novel Adenosine Monophosphate-activated Protein Kinase (AMPK) Activator

Lee

Hsu

Guh

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Adenosine monophosphate-activated protein kinase (AMPK) modulates cancer cell metabolism and survival. Results: The novel compound OSU-53 directly activates AMPK, inhibits multiple metabolic and oncogenic pathways, and induces apoptosis in triple-negative breast cancer cells. Conclusion: OSU-53 acts through a broad spectrum of antitumor activities downstream of AMPK activation. Significance: OSU-53 is a potent small molecule AMPK activator with translational potential for breast cancer therapy.

show abstract

Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma

Cited by 253 publications

References 72 publications

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

Targeting Energy Metabolic and Oncogenic Signaling Pathways in Triple-negative Breast Cancer by a Novel Adenosine Monophosphate-activated Protein Kinase (AMPK) Activator

Contact Info

Product

Resources

About