Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition

Towers, Christina G.; Fitzwalter, Brent E.; Regan, Daniel P.; Goodspeed, Andrew; Morgan, Michael J.; Liu, Changwei; Gustafson, Daniel L.; Thorburn, Andrew

doi:10.1016/j.devcel.2019.07.010

Cited by 78 publications

(95 citation statements)

References 67 publications

(86 reference statements)

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“…Cell Uptake Experiments 4 human breast cancer cell lines were used to perform experiments. The first 2, MBA-MB-231 and MDA-MB-468, are mechanistically sensitive to autophagy inhibition through gene knockdown (Maycotte et al, 2014;Towers et al, 2019) and pharmacologically sensitive to hydroxychloroquine. The second 2, MCF7 and T47D, are insensitive to both methods (Maycotte et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition

Collins

Witta

Coy

et al. 2020

J Pharmacol Exp Ther

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Section: Introductionmentioning

confidence: 99%

Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition

Collins

Witta

Coy

et al. 2020

J Pharmacol Exp Ther

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“…Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway can not only response to cellular stress, but also activate Nrf2-dependent transcriptional programs to further promote cancer hallmark proteins [17]. Cancer cells via facilitating Nrf2 signaling to circumvent the inhibition of autophagy, which means the activation of Nrf2 signaling acts as a protection of cancer cells [18]. Janus kinase 2 (JAk2) signaling pathway has participated in regulating immune system and cell growth [19].…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer

Guo

Zhu

Wang

et al. 2020

BMC Complement Med Ther

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Background: Pancreatic cancer is aggressive with no symptoms until the advanced stage reached. The increased resistance of pancreatic cancer to chemotherapy demonstrates a dilemma in the clinical field. Hence, it is a matter of great urgency to develop an effective drug to treat patients with pancreatic cancer. Betulinic acid is a major triterpene isolated from spina date seed. Several studies have suggested its low toxicity and side effects to patients with malaria and inflammation. However, relevant studies on betulinic acid in inhibiting cancer were insufficient and the molecular mechanism was unclear. This study aimed to systematically explore the potential anti-cancer functions of betulinic acid in pancreatic cancer, and investigate its underlying molecular mechanism. Methods: The Counting Kit-8 assay, colony formation, transwell invasion assay, wound healing assay, flow cytometry and xenograft nude mice model were used to evaluate the effect of betulinic acid on the proliferation, invasion and migration ability of pancreatic cancer cells. Results: Our results showed that betulinic acid obviously suppressed pancreatic cancer both in vitro and in vivo in a dose-dependent manner. We also determined that betulinic acid inhibited pancreatic cancer by specifically targeting mTOR signaling rather than Nrf2 or JAK2. Conclusions: These findings clarify that betulinic acid is a potential and valuable anticancer agent for pancreatic cancer, and indicate the specific molecular target of betulinic acid.

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“…But, even in autophagy-dependent cell lines where CRISPR-mediated KO of ATG7 caused the majority of the cells to die within 48 h after editing, at much later time points ATG7-deficient clones could be isolated. Intriguingly, the selected ATG7 −/− clones that were derived from autophagy-dependent cells grew at equal rates compared to the WT cells from which they were derived, even in autophagy-inducing conditions such as nutrient starvation or hypoxia (Towers et al, 2019). These adapted cells were also resistant to pharmacological inhibitors of autophagy such as CQ.…”

Section: Adaptation To Autophagy Inhibitionmentioning

confidence: 99%

“…Moreover, a recent genome-wide CRISPR screen showed that KO of a large subset of autophagy genes results in up-regulation of the NRF2 signaling pathway (Kerins et al, 2019). As a consequence of NRF2 up-regulation, the autophagy-deficient cells developed an increased sensitivity to pharmacological proteasome inhibitors, a phenotype that was exacerbated with NRF2 knockdown (Towers et al, 2019). These results suggest that tumors that originally start off sensitive to pharmacological autophagy inhibition may be able to adapt and acquire mechanisms of resistance to these therapies.…”

Section: Adaptation To Autophagy Inhibitionmentioning

confidence: 99%

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

2019

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Autophagy is intricately linked with many intracellular signaling pathways, particularly nutrient-sensing mechanisms and cell death signaling cascades. In cancer, the roles of autophagy are context dependent. Tumor cell–intrinsic effects of autophagy can be both tumor suppressive and tumor promotional. Autophagy can therefore not only activate and inhibit cell death, but also facilitate the switch between cell death mechanisms. Moreover, autophagy can play opposing roles in the tumor microenvironment via non–cell-autonomous mechanisms. Preclinical data support a tumor-promotional role of autophagy in established tumors and during cancer therapy; this has led to the launch of dozens of clinical trials targeting autophagy in multiple cancer types. However, many questions remain: which tumors and genetic backgrounds are the most sensitive to autophagy inhibition, and which therapies should be combined with autophagy inhibitors? Additionally, since cancer cells are under selective pressure and are prone to adaptation, particularly after treatment, it is unclear if and how cells adapt to autophagy inhibition. Here we review recent literature addressing these issues.

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Cancer Cells Upregulate NRF2 Signaling to Adapt to Autophagy Inhibition

Cited by 78 publications

References 67 publications

Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition

Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition

Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer

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

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