Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Iwamaru, Arifumi; Kondo, Yasuko; Iwado, Eiji; Aoki, Hiroshi; Fujiwara, Keishi; Yokoyama, Tomohisa; Mills, Gordon B.; Kondo, Seiji

doi:10.1038/sj.onc.1209992

Cited by 137 publications

(107 citation statements)

References 44 publications

(57 reference statements)

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“…In contrast, inactivation of mTORC1 and mTORC2 by stable RNA interference against mTOR sensitized LNT-229 cells against induction of autophagy and cell death triggered by (−)-gossypol and (−)-gossypol in combination with TMZ. These data suggest that mTORC2 has an essential contributory role in the inhibition of autophagy and autophagydependent cell death in glioma cells (62). In a reciprocal fashion to our results obtained with the mTOR-KD cells, knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells potently diminished the extent of cell death induced by (−)-gossypol and the combined treatment with TMZ, indicating that autophagy indeed significantly contributed to this type of cell death.…”

Section: Discussionsupporting

confidence: 73%

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Voss

Senft

Lang

et al. 2010

Molecular Cancer Research

171

145

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Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O 6 -methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1.

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Section: Discussionsupporting

confidence: 73%

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

Voss

Senft

Lang

et al. 2010

Molecular Cancer Research

171

145

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“…Several studies have shown that the inhibition of Akt phosphorylation and its downstream mTOR signaling target contribute to the initiation of autophagy. 30,[55][56][57] However, Fig. 8 clearly shows that harmol treatment did not affect the phosphorylation of Akt (neither Ser473 nor Thr 308), but the level of p-mTOR (Ser2448), downstream from Akt, transiently increased for 2 to 4 h, and then decreased to the control level.…”

Section: Discussionmentioning

confidence: 96%

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

Abe

Yamada

Moriya

et al. 2011

Biological & Pharmaceutical Bulletin

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Lung cancer is a leading cause of death worldwide, and the long-term survival rate of lung cancer patients is one of the lowest among cancers.1,2) Two major types of lung cancer have been identified: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC, the most prevalent subtype, is relatively resistant to chemotherapy and radiation therapy. On the other hand, SCLC is initially highly sensitive to chemotherapy and radiation therapy, but shows resistance to treatment in the majority of patients.3) The high mortality in NSCLC is due to the difficulty of early diagnosis and its high potential for local invasion and distant metastasis. Although relatively effective chemotherapeutic agents have been developed, lung cancer still has a low cure rate. Furthermore, the adverse effects of chemotherapeutic compounds often hamper the quality of life of lung cancer patients. Therefore, the discovery of effective novel prophylactic, diagnostic, and therapeutic treatments for NSCLC is urgently needed."Apoptosis" has been used as a synonym for programmed cell death (PCD), and is a well-known form of PCD. Since the 1960s, various morphological forms of PCD have been recognized. Clarke classified cell death into 4 types, including type I PCD (apoptosis) and type II PCD (autophagy). 4)Numerous studies have demonstrated that most chemotherapy agents and certain naturally occurring compounds induce cell death by activating the apoptotic pathway. It is thought that apoptosis induction in tumor cells with either drugs or natural products is effective therapy for cancer and immune system diseases. On the other hand, autophagy is one of the major regulatory mechanisms in the degradation of intracellular proteins and organelles. 5,6) During autophagy, the cytosol and whole organelles become encased in double-membrane vacuoles such as autophagosomes, and subsequently fuse with lysosomes.5) Degradation of the sequestered material generates nucleotides, amino acids, and free fatty acids that are recycled for macromolecular synthesis and ATP generation.7) Although originally characterized as a survival response to nutrient deficiency, autophagy is now recognized as frequently induced in response to a variety of stressors to maintain cellular homeostasis. [8][9][10][11][12] In recent years, the importance of autophagy has been emphasized in various biological fields, including cancer. 9,[13][14][15] Furthermore, cancer cells show less autophagy than normal cells. 16,17) These findings indicate that autophagy induction is an attractive modality of anticancer therapy.b-Carboline alkaloids occur in a number of medicinal plants such as Peganum harmala, Passiflora edulis, Passiflora incarnata, and Banisteriopsis caapi.18,19) These plants have been used in traditional medicine to treat asthma, jaundice, lumbago, and other human ailments.19-21) Recently, it has been reported that certain b-carboline alkaloids and their related compounds have cytotoxic effects on cancer cells. [22][23][24] We also reported previously that harm...

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“…Akt inhibition also strongly promotes autophagy whereas constitutively active Akt has the opposite action (Laane et al, 2009). Inhibitors of mTOR have also been shown to induce autophagy in various cell types (Paglin et al, 2005;Cao et al, 2006;Iwamaru et al, 2007). In addition, stabilization of TSC2, which inhibits the mTOR signaling, promotes autophagy and suppresses tumorigenesis (Kuo et al, Figure 1 Cellular mechanism and regulators of autophagy.…”

Section: Regulation Of Autophagy By Oncogenic and Tumor-suppressing Pmentioning

confidence: 99%

The autophagic paradox in cancer therapy

et al. 2011

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Autophagy, hallmarked by the formation of doublemembrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in earlystage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a prosurvival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cellfate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.

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Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells

Cited by 137 publications

References 44 publications

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma

The .BETA.-Carboline Alkaloid Harmol Induces Cell Death via Autophagy but Not Apoptosis in Human Non-small Cell Lung Cancer A549 Cells

The autophagic paradox in cancer therapy

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