Autophagy and cancer: Modulation of cell death pathways and cancer cell adaptations

Towers, Christina G.; Wodetzki, Darya; Thorburn, Andrew

doi:10.1083/jcb.201909033

Cited by 94 publications

(97 citation statements)

References 156 publications

(198 reference statements)

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“…Considering the role of autophagy in cancer pathogenesis, we investigated whether CPT can modulate the autophagic signaling cascade. Autophagy is a degrading process in which autophagosomes package damaged organelles or cellular debris fused with lysosomes for degradation ( Levy et al, 2017 ; Towers et al, 2019 ). LC3, a widely used marker, plays a crucial role in autophagosome biogenesis and autophagy substrate selection ( Shi et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Mechanisms of Cryptotanshinone as a Therapeutic Agent Against Hepatocellular Carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is a fatal and dominant form of liver cancer that currently has no effective treatment or positive prognosis. In this study, we explored the antitumor effects of cryptotanshinone (CPT) against HCC and the molecular mechanisms underlying these effects using a systems pharmacology and experimental validation approach. First, we identified a total of 296 CPT targets, 239 of which were also HCC-related targets. We elucidated the mechanisms by which CPT affects HCC through multiple network analysis, including CPT-target network analysis, protein-protein interaction network analysis, target-function network analysis, and pathway enrichment analysis. In addition, we found that CPT induced apoptosis in Huh7 and MHCC97-H ells due to increased levels of cleaved PARP, Bax, and cleaved caspase-3 and decreased Bcl-2 expression. CPT also induced autophagy in HCC cells by increasing LC3-II conversion and the expression of Beclin1 and ATG5, while decreasing the expression of p62/SQSTM1. Autophagy inhibitors (3-methyladenine and chloroquine) enhanced CPT-induced proliferation and apoptosis, suggesting that CPT-induced autophagy may protect HCC cells against cell death. Furthermore, CPT was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Interestingly, activation of PI3K by insulin-like growth factor-I inhibited CPT-induced apoptosis and autophagy, suggesting that the PI3K/AKT/mTOR signaling pathway is involved in both CPT-induced apoptosis and autophagy. Finally, CPT was found to inhibit the growth of Huh7 xenograft tumors. In conclusion, we first demonstrated the antitumor effects of CPT in Huh7 and MHCC97-H cells, both in vitro and in vivo . We elucidated the potential antitumor mechanism of CPT, which involved inducing apoptosis and autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway. Our findings may provide valuable insights into the clinical application of CPT, serving as a potential candidate therapeutic agent for HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Uncovering the Mechanisms of Cryptotanshinone as a Therapeutic Agent Against Hepatocellular Carcinoma

et al. 2020

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“…Then the transmission electron microscope observation combined with western blotting assay were used to confirm that DEH did cause endoplasmic reticulum stress in colorectal cancer cells in dose-and time-dependent manner. According to the previous reports, endoplasmic reticulum stress not only can increase autophagy but also can make autophagy inhibition [47,48].…”

Section: Discussionmentioning

confidence: 92%

Dehydrodiisoeugenol Inhibits Colorectal Cancer Growth by Endoplasmic Reticulum Stress Induced Autophagic Pathways

Li¹,

Zhang²,

Pan³

et al. 2020

Preprint

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Dehydrodiisoeugenol (DEH), a novel lignan component extracted from the Nutmeg seeds, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anti-cancer activity in gastrointestinal cancer is still to be investigated. Here, the anti-cancer effect of DEH to human colorectal cancer and its underlying mechanism were evaluated. The DEH treatment arrests the cell cycle of colorectal cancer cells at G1/S phase, which leading to a significant cell growth inhibition. Moreover, it can induce strong cellular autophagy and the autophagy would be inhibited through autophagic inhibitors with reducing EDH-induced inhibition of cell growth in colorectal cancer cells. Further studies indicated that DEH can also induce endoplasmic reticulum (ER) stress, and could subsequently stimulating autophagy through activating PERK/eIF2α and IRE1α/XBP-1s/CHOP pathways. Knockdown of PERK or IRE1α can significantly decrease the DEH-induced autophagy and retrieve cell viability in cells treated with DEH. What’s more, DEH exhibits significant anti-cancer activities through CDX- and PDX-model as well. Taken together, our studies strongly suggest that DEH might be a potential anti-cancer agent against colorectal cancer via activating ER stress-induced autophagy inhibition.

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“…In general, autophagy has been widely considered as a tumor suppressor mechanism at the stage of carcinogenesis, while tumor-promoting role of autophagy has been associated with progression of cancer, including melanoma [55,[64][65][66]. It has been demonstrated that autophagy suppressed melanomagenesis by promoting senescence, and decreased expression of ATG5 was sufficient to preclude this process [67].…”

Section: Autophagy In Melanomamentioning

confidence: 99%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

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Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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Autophagy and cancer: Modulation of cell death pathways and cancer cell adaptations

Cited by 94 publications

References 156 publications

Uncovering the Mechanisms of Cryptotanshinone as a Therapeutic Agent Against Hepatocellular Carcinoma

Uncovering the Mechanisms of Cryptotanshinone as a Therapeutic Agent Against Hepatocellular Carcinoma

Dehydrodiisoeugenol Inhibits Colorectal Cancer Growth by Endoplasmic Reticulum Stress Induced Autophagic Pathways

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

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