The role of autophagy in cancer development and response to therapy

Kondo, Yasuko; Kanzawa, Takao; Sawaya, Raymond; Kondo, Seiji

doi:10.1038/nrc1692

Cited by 1,568 publications

(1,549 citation statements)

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“…In cancer research, autophagy is a novel concept, and its therapeutic role remains unclear (Ogier-Denis and Codogno, 2003;Gozuacik and Kimchi, 2004;Kondo et al, 2005). In this study, we demonstrated that inhibition of rapamycin-induced autophagy by Beclin 1 siRNA attenuated rapamycin's cytotoxicity, indicating that rapamycin-induced autophagy likely mediates, at least in part, the antitumor effects of rapamycin.…”

Section: Discussionmentioning

confidence: 70%

“…Effect of inhibiting rapamycin-induced autophagy by Beclin 1 siRNA on malignant glioma cells Whether cancer treatment-induced autophagy mediates anticancer activity or functions as a protective reaction against the treatment remains controversial (OgierDenis and Codogno, 2003;Gozuacik and Kimchi, 2004;Kondo et al, 2005). To assess the role of autophagy in rapamycin cytotoxicity, we determined whether inhibition of autophagy alters rapamycininduced cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, less autophagic degradation is seen in cancer cells than in their normal counterparts. Therefore, autophagy is thought to be a tumor suppressor mechanism (OgierDenis and Codogno, 2003; Gozuacik and Kimchi, 2004; Kondo et al, 2005) based on the findings that Beclin 1 is a haploinsufficient tumor suppressor gene that regulates autophagy (Liang et al, 1999;Qu et al, 2003;Yue et al, 2003). Because Beclin 1 siRNA inhibited rapamycininduced autophagy and reduced its antitumor effect but did not induce apoptosis in rapamycin-sensitive tumor cells, we speculated that Beclin 1 plays a role in rapamycin-induced autophagy, which suppresses growth of malignant glioma cells.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2006

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The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of malignant glioma cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as promising therapy for malignant gliomas. However, the efficacy of mTOR inhibitors alone in the treatment of patients with malignant gliomas is only modest, potentially because these agents rather than acting as mTOR kinase inhibitors instead interfere with the function of only mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not perturb all mTOR functions. The purpose of this study was to determine whether global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin on malignant glioma cells. We showed that rapamycin induced autophagy and that inhibition of autophagy by small interfering RNA (siRNA) directed against autophagyrelated gene Beclin 1 attenuated the cytotoxicity of rapamycin in rapamycin-sensitive tumor cells, indicating that the autophagy was a primary mediator of rapamycin's antitumor effect rather than a protective response. Exogenous expression of an mTOR mutant interfering with its kinase activity markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on tumor cell viability by stimulating autophagy. Importantly, not only rapamycin-sensitive malignant glioma cells with PTEN mutations but also rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy is one of the agent's antitumor effects and that silencing or inhibiting mTOR kinase activity could enhance the effectiveness of rapamycin.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

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

et al. 2006

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“…The role of drug-induced autophagy in cell death or survival is therefore unresolved. 3,8 Temozolomide (TMZ) is an alkylating agent which is widely used for treating primary and recurrent high-grade gliomas. 9 The cytotoxicity of TMZ is thought to result from the formation of O 6 -methylguanine in DNA, which mispairs with thymine during DNA replication triggering futile cycles of the mismatch repair system and subsequent DNA damage.…”

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confidence: 99%

“…5 It is also known that autophagy is induced in cancer cells derived from tissues such as breast, colon, prostate and brain in response to a variety of anticancer therapies. 3,8 However, autophagy in response to these drugs can produce different outcomes, in some cases promoting cell adaptation and survival similar to what is seen in nutrient deprived cells, while in other cases, inducing programmed cell death type. The role of drug-induced autophagy in cell death or survival is therefore unresolved.…”

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confidence: 99%

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

et al. 2006

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Although autophagy enhances cell survival in nutrient-deprived cells by increasing adenosine triphosphate (ATP) production, it remains unclear if autophagy functions similarly in cells treated with cytotoxic chemotherapy agents. To address this issue, we measured both the ability of DNA damaging agents (Temozolomide, and Etoposide) to induce an autophagy-dependent production of ATP, and the effects of modulation of autophagy on drug-induced cell death. Both drugs induced an autophagyassociated increase in ATP production in multiple glioma cell lines. The drug-induced ATP surge could not be blocked by glucose starvation, but could be blocked by preincubation with the autophagy inhibitor 3-methyladenine (3-MA), an siRNA targeting beclin 1, or the mitochondrial inhibitor oligomycin. Inhibition of autophagy-induced ATP production increased nonapoptotic cell death associated with micronucleation, while restoration of the 3-MA-inhibited ATP surge by addition of pyruvate suppressed cell death. These results show that DNA damaging agents induce an autophagy-associated ATP surge that protects cells and may contribute to drug resistance. Autophagy is a process by which subcellular constituents are degraded in autophagosomes/autolysosomes in response to stress. 1 Whereas growth factors enhance the ability of metazoan cells to take up extracelluar nutrients and suppress autophagy, deprivation of either growth factors or extracellular nutrients leads to decreased nutrient uptake and derepression of autophagy. The catabolic autophagy process is believed to allow starving cells to support adenosine triphosphate (ATP) production and avoid cell death. 2,3 The autophagic process is regulated by both class I and class III phosphatidylinositol 3-kinase (PI3K) pathways. 2,4,5 Mammalian target of Rapamycin (mTOR) functions downstream of the class-I PI3K/Akt, and is a key negative regulator of autophagy. In this role, mTOR serves as a metabolic sensor that coordinates crosstalk between nutrient availability and autophagy. 6,7 In contrast, class III PI3K positively regulates autophagy. The formation of a preautophagosomal isolation membrane that encloses cytoplasmic cargo is positively regulated by phosphatidylinositol 3-phosphate, the products of class III PI3K phosphorylation. 4 It has also been suggested that the trafficking of autophagosomes is regulated by class III PI3Ks, 4,5 an idea supported by the observation that 3-methyladenine (3-MA), which inhibits class III PI3K activity, also inhibits autophagosome formation and is widely used as an autophagy inhibitor. 5 It is also known that autophagy is induced in cancer cells derived from tissues such as breast, colon, prostate and brain in response to a variety of anticancer therapies. 3,8 However, autophagy in response to these drugs can produce different outcomes, in some cases promoting cell adaptation and survival similar to what is seen in nutrient deprived cells, while in other cases, inducing programmed cell death type. The role of drug-induced autophagy in cell death or surv...

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p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

Taniguchi

Yamachika

et al. 2016

FEBS Letters

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p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.

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The role of autophagy in cancer development and response to therapy

Cited by 1,568 publications

References 76 publications

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

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

DNA damaging agent-induced autophagy produces a cytoprotective adenosine triphosphate surge in malignant glioma cells

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

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