Autophagy and metastasis: another double-edged sword

Kenific, Candia M.; Thorburn, Andrew; Debnath, Jayanta

doi:10.1016/j.ceb.2009.10.008

Cited by 262 publications

(253 citation statements)

References 33 publications

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“…Autophagy can favor cell survival or on the B10 triggers destructive autophagy P Gonzalez et al contrary can promote cell death under stress conditions. 18,19 Importantly, PI3K/Akt/mTOR inhibition per se is not cytotoxic in U87MG cells as we and others previously reported, 20,21 but recent evidence indicates that late-stage disruption of the autophagic process can cause detrimental autophagy. 21 Therefore, the role of autophagy in B10-induced cell death was addressed by RNAi-mediated knockdown of ATG7, ATG5 or BECN1, key regulators of autophagy.…”

Section: Resultsmentioning

confidence: 61%

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Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

et al. 2012

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In this study, we report a novel mechanism of action for a cytotoxic derivative of betulinic acid (BA). B10 is a semi-synthetic glycosylated derivative of BA selected for its enhanced cytotoxic activity. Interestingly, although B10 induces apoptosis, caspase-3 downregulation incompletely prevents B10-induced cell death, Bcl-2 overexpression fails to protect cells and DNA fragmentation rates do not reflect cell death rates in contrast to cytoplasmic membrane permeabilization. These results implicate that apoptotic and non-apoptotic cell death coexist upon B10 treatment. Unexpectedly, we found that B10 induces autophagy and also abrogates the autophagic flux. B10 destabilizes lysosomes as shown by Lysotracker Red staining and by cathepsin Z and B release from lysosomes into the cytoplasm. Consistently, the cathepsin inhibitor Ca074Me significantly decreases B10-induced cell death, further supporting the fact that the release of lysosomal enzymes contributes to B10-triggered cell death. Downregulation of ATG7, ATG5 or BECN1 by RNAi significantly decreases caspase-3 activation, lysosomal permeabilization and cell death. Thus, by concomitant induction of autophagy and inhibition of the autophagic flux, B10 turns autophagy into a cell death mechanism. These findings have important implications for the therapeutic exploitation of BA derivatives, particularly in apoptosis-resistant cancers. Bioactive natural compounds or their semi-synthetic derivatives offer a considerable therapeutic potential against cancer.1 Among these, betulinic acid (BA), a triterpenoid initially derived from white birch tree, has received attention because of its multiple biological activities in mammalian cells. The pluripotency of BA is of great interest, as this compound is active against HIV, parasitic diseases and cancer.2-5 Nevertheless, the therapeutic application of this drug is currently limited because of its poor solubility in aqueous solvents and an ill-defined mode of action. To overcome these limitations, a wide variety of semi-synthetic derivatives of BA has been generated to improve its pharmacological properties for in vivo studies. In addition, detailed studies are being performed to elucidate the mechanisms of action underlying their cytotoxic activity. To date, BA and its derivatives have been reported to induce cell death in cancer cells via the activation of the intrinsic pathway of apoptosis.6 Accordingly, BA triggers the release of pro-apoptotic factors, such as cytochrome-c, from the mitochondria supposedly by interacting with the permeability pore transition complex and by modifying the balance of pro-and anti-apoptotic proteins of the Bcl-2 protein family. 6 In addition, BA and its derivatives appear to interfere with multiple signaling pathways involved in survival. PI3K, NF-kB and lipid metabolism are modulated by BA-related compounds, but whether and how these effects contribute to cell death is unknown.7-10 A better understanding of the mechanism of action of these compounds is critical to promote their therapeutic...

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Section: Resultsmentioning

confidence: 61%

“…18,19 Importantly, autophagy contributes to B10-induced cell death as silencing of autophagy genes, such as ATG5, ATG7 or BECN1, reduces cell death following treatment with B10. Although induction of autophagy is required to promote cell death upon B10 treatment, this is per se insufficient for cell death execution.…”

Section: Discussionmentioning

confidence: 99%

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

et al. 2012

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“…BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton (Agostinis et al, 2013). Furthermore, autophagy itself can promote tumor metastasis (Kenific et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

High Expression of HIF-1α, BNIP3 and PI3KC3: Hypoxia-Induced Autophagy Predicts Cholangiocarcinoma Survival and Metastasis

Thongchot

Yongvanit²,

Loilome³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Hypoxia and autophagy are known to facilitate tumor progression. We here aimed to investigate the role of hypoxia-associated autophagy in cholangiocarcinoma (CCA) survival and metastasis. Immunostaining of hypoxicresponsive proteins (HIF-1α and BNIP3) and a key regulator of autophagy (PI3KC3) were examined in CCA tissues and their expression levels were compared with clinicopathological parameters. A hypoxia mimicking condition (CoCl 2 treatment) was also tested regarding CCA cell functions. Our results showed that HIF-1α (66%), BNIP3 (44%) and PI3KC3 (46%) showed strong staining in human CCA tissues. Positive expression of HIF-1α (p=0.033), BNIP3 (p=0.040) and PI3KC3 (p=0.037) was significantly correlated with lymph node metastasis. HIF-1α was well associated with BNIP3 (r=0.3, p<0.01) and PI3KC3 (r=0.2, p<0.01). The survival rates of patients who were positive with HIF-1α (p=0.047) or co-expressed HIF-1α and BNIP3 (p=0.032) or HIF-1α and PI3KC3 (p=0.043) were significantly greater than in the negative groups. CCA cells treated with CoCl 2 showed an increase in HIF-1α, BNIP3, PI3KC3 and LC3-II, with increased cell migration and pFAK levels. These data suggest that hypoxia associated autophagy enhances CCA metastasis, resulting in a poor prognosis of CCA.

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“…The cancer cells undergo malignant transformation, and can be transferred through blood or lymphatic circulation to a distant location. Autophagy may cooperate with the stimulation signals to bypass anoikis and promote metastasis (Kenific et al, 2010). In a 3D culture model of MCF-10A, Atg5 or Atg7 knockdown induced the luminal apoptosis, indicating that autophagy promotes epithelial cell survival during anoikis (Fung et al, 2008).…”

Section: Balance Between Autophagy and Anoikis Resistance In Solid Camentioning

confidence: 99%

Integration of Autophagy and Anoikis Resistance in Solid Tumors

Yang¹,

Zheng

Yan³

et al. 2013

The Anatomical Record

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Macroautophagy or autophagy is a lysosome-dependent process in which enzymatic degradation and recycling of cytosolic components occurred due to stressful conditions. This cellular arrangement imparts anoikis resistance in solid tumors. Anoikis, a special form of apoptosis occurring when cells detach from the extracellular matrix, is a critical mechanism in maintaining tissue homeostasis and development. Anoikis resistance facilitates tumorigenesis and metastasis. However, the complexity of the role of autophagy in tumor is underscored by evidence that autophagy can function as both a pro-survival or pro-death depending on the context and the stimuli, which are likely exploitable for tumor therapy. This review focuses on recent progress in understanding anoikis resistance and autophagy signaling, paying particular attention to its relevance in solid tumor metastasis. Anat Rec, 296:1501Rec, 296: -1508

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Autophagy and metastasis: another double-edged sword

Cited by 262 publications

References 33 publications

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process

High Expression of HIF-1α, BNIP3 and PI3KC3: Hypoxia-Induced Autophagy Predicts Cholangiocarcinoma Survival and Metastasis

Integration of Autophagy and Anoikis Resistance in Solid Tumors

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