ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth

Hart, Lori S.; Cunningham, J. T.; Datta, Tatini; Dey, Souvik; Tameire, Feven; Lehman, Stacey L.; Qiu, Bo; Zhang, Haiyan; Cerniglia, George J.; Bi, Meixia; Li, Yan; Gao, Yan; Liu, Huayi; Li, Changhong; Maity, Amit; Thomas-Tikhonenko, Andrei; Perl, Alexander E.; Koong, Albert C.; Fuchs, Serge Y.; Diehl, J. Alan; Mills, Ian G.; Ruggero, Davide; Koumenis, Constantinos

doi:10.1172/jci62973

Cited by 348 publications

(325 citation statements)

References 69 publications

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“…Previously, several studies have shown PBA, a well-known chemical chaperone, inhibited ER stress-mediated apoptosis. 40,41 In accordance with these reports, we showed that PBA alleviates ER stress response induced by aldosterone in podocytes. Treatment with PBA downregulated UPR-related proteins including Bip, grp94, and Chop.…”

Section: Discussionsupporting

confidence: 91%

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

Yuan

Zhao

et al. 2015

Laboratory Investigation

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Podocytes play an important role in the pathogenesis and progression of glomerulosclerosis. Recent studies indicate that aldosterone/mineralocorticoid receptor (MR) is a major contributor of chronic kidney disease (CKD) progression. Aldosterone/MR induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria. The present study investigated the mechanisms by which aldosterone/MR mediated podocyte injury, focusing on the involvement of oxidative stress, endoplasmic reticulum (ER) stress, and autophagy. We observed that aldosterone/ MR induced ER stress and podocyte injury both in vivo and in vitro. Blockade of ER stress significantly reduced aldosterone/ MR-induced podocyte injury. In addition, we found that ER stress-induced podocyte injury was mediated by CCAAT/ enhancer-binding protein (C/EBP) homologous protein (Chop). Interestingly, autophagy was also enhanced by aldosterone/MR. Pharmacological inhibition of autophagy resulted in increased apoptosis. Inhibition of ER stress significantly reduced aldosterone/MR-induced autophagy. In addition, the activation of ER stress increased the formation of autophagy, which protected podocytes from apoptosis. Moreover, we observed that the addition of ROS scavenger, N-acetyl cystein (NAC), blocked both ER stress and autophagy by aldosterone/MR. Collectively, these results suggest that oxidant stress-mediated aldosterone/MR-induced podocyte injury via activating ER stress, which then triggers both Chop-dependent apoptosis and autophagy to cope with the injury. These findings may guide us to therapeutic strategies for glomerular diseases.

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Section: Discussionsupporting

confidence: 91%

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

Yuan

Zhao

et al. 2015

Laboratory Investigation

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“…Instead, signaling due to increased ER stress drives autophagy independent of the mTOR pathway in these cells. The unfolded protein response has previously been linked to induction of autophagy in disease contexts like cancer and neurodegenerative diseases (43,44). Signaling through both the PERK-and IRE-dependent arms of the unfolded protein response has been linked with induction of autophagy (for review see Ref.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

Kwartler

Chen

Thakur

et al. 2014

Journal of Biological Chemistry

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Background: Genomic duplications involving the smooth muscle myosin heavy chain gene, MYH11, are associated with increased risk for acute aortic dissections. Results: MYH11 overexpression causes increased turnover of contractile proteins through increased autophagy. Conclusion: MYH11 duplications may predispose to aortic disease through increased turnover of contractile proteins and disruption of contractile signaling. Significance: Increased protein turnover may be an important mechanism by which genomic duplications cause human disease.

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“…21 In addition, ER stress has proved to be one of the inducers of autophagy. 22 Interestingly, DHA induced-ER stress has been observed in several tumor cells, 23,24 and our previous studies have demonstrated that DHA both induce apoptosis and autophagy in various cancer cells. 25,26 The Complex relationships among ER stress, autophagy and apoptosis remain unclear, but it's perhaps noteworthy that we found p8 is involved in all of these 3 biological functions induced by DHA.…”

Section: Introductionmentioning

confidence: 93%

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

Chen

Zeng

et al. 2015

Cancer Biology & Therapy

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Dihydroartemisinin (DHA) exhibits anticancer activities in a variety of cancer cells, but DHA alone are not effective enough for cancer therapy. In this study we found the stress-regulated protein p8 was obviously increased after DHA treatment in several cancer cells, which further to induce autophagy by the upregulation of endoplasmic reticulum stress-related protein ATF4 and CHOP. Furthermore, when we silenced p8 by siRNA in cancer cells, the apoptosis induced by DHA were notably increased, whereas the overexpression of p8 in cancer cells leaded to the resistance to DHA-induced apoptosis. Moreover, we found the inhibition of autophagy with chloroquine (CQ) can enhance the anticancer effect of DHA both in vitro and in vivo. In conclusion, we found that p8-mediated autophagy attenuates DHA-induced apoptosis in cancer cells, which provides evidence to support the use p8 as a cancer therapeutic target, and suggests that the combination treatment with DHA and autophagy inhibitor might be an effective cancer therapeutic strategy.

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ER stress–mediated autophagy promotes Myc-dependent transformation and tumor growth

Abstract: The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cel-

Cited by 348 publications

References 69 publications

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

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