A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy

He, W; Wang, Q; Srinivasan, B; Xu, J; Padilla, M T; Li, Z; Wang, X; Liu, Y; Gou, X; Shen, H-M; Xing, C; Lin, Y

doi:10.1038/onc.2013.256

Cited by 124Cell death mechanisms and regulationAutophagy in Disease and TherapyNatural Compounds in Disease Treatment

A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy

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He, W, Wang, Q, Srinivasan, B, Xu, J, Padilla, M T, Li, Z, Wang, X, Liu, Y +4 more·2014·Oncogene

DOI 10.1038/onc.2013.256PMC PMC3912228

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Abstract

Killing cancer cells through the induction of apoptosis is one of the main mechanisms of chemotherapy. However, numerous cancer cells have primary or acquired apoptosis resistance, resulting in chemoresistance. In this study, using a novel chalcone derivative chalcone-24 (Chal-24), we identified a novel anticancer mechanism through autophagy-mediated necroptosis (RIP1- and RIP3-dependent necrosis). Chal-24 potently killed different cancer cells with induction of necrotic cellular morphology while causing no detectable caspase activation. Blocking the necroptosis pathway with either necrostatin-1 or by knockdown of RIP1 and RIP3 effectively blocked the cytotoxicity of Chal-24, suggesting that Chal-24-induced cell death is associated with necroptosis. Chal-24 robustly activated JNK and ERK and blockage of which effectively suppressed Chal-24-induced cytotoxicity. In addition, Chal-24 strongly induced autophagy that is dependent on JNK-mediated phosphorylation of Bcl-2 and Bcl-xL and dissociation of Bcl-2 or Bcl-xL from Beclin-1. Importantly, suppression of autophagy, with either pharmacological inhibitors or small interfering RNAs targeting the essential autophagy components ATG7 and Beclin-1, effectively attenuated Chal-24-induced cell death. Furthermore, we found that autophagy activation resulted in c-IAP1 and c-IAP2 degradation and formation of the Ripoptosome that contributes to necroptosis. These results thus establish a novel mechanism for killing cancer cells that involves autophagy-mediated necroptosis, which may be employed for overcoming chemoresistance.

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Necroptosis is favored by a necrosome-scaffolding function of the autophagy apparatus and by autophagic degradation of c-IAP1 and c-IAP2.
“necroptosis, which is favored by a necrosome-scaffolding function of the autophagy apparatus [823–825], as well as by the autophagic degradation of c-IAP1 and c-IAP2 [826].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [826]

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Background
Cell death in drug-induced liver injury
Iorga, A., & Dara, L. (2019) · Advances in pharmacology · doi:10.1016/bs.apha.2019.01.006 · Cited by 87 · see citing works
Ripening-induced chemical modifications of papaya pectin inhibit cancer cell proliferation
do Prado, S. B. R., Ferreira, G. F., Harazono, Y., Shiga, T. M., Raz, A., Carpita, N. C., & Fabi, J. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-16709-3 · Cited by 86 · see citing works
Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway
Zhou, H., Shen, T., Shang, C., Luo, Y., Liu, L., Yan, J., Li, Y., & Huang, S. (2014) · Oncotarget · doi:10.18632/oncotarget.2471 · Cited by 84 · see citing works
FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells
Zhang, L., Wang, H., Ding, K., & Xu, J. (2015) · Toxicology Letters · doi:10.1016/j.toxlet.2015.04.015 · Cited by 84 · see citing works
“Under certain conditions, autophagy servers as an upstream of necroptosis (He et al., 2013).”
BackgroundSelf-citation
RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy
Luan, Q., Jin, L., Jiang, C. C., Tay, K. H., Lai, F., Liu, X., Liu, Y. L., Guo, S., Li, C. Y., Yan, X. G., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1049800 · Cited by 81 · see citing works
“We also tested whether MAPK8/9-mediated activation of autophagy leads to formation of the ripoptosome and triggers necroptosis in melanoma cells undergoing pharmacological ER stress, as does it in other types of cancer cells under different conditions.(50) Exposure of Mel-RM and MM200 cells to TM or TG did not affect…”
BackgroundSelf-citation
Cancer and necroptosis: friend or foe?
Philipp, S., Sosna, J., & Adam, D. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2193-2 · Cited by 74 · see citing works
“As a control, inhibition of autophagy effectively suppressed the association of FADD and caspase-8 with RIP1 and thereby formation of the ripoptosome [81].”
Background
Platycodin D induces apoptosis and triggers ERK- and JNK-mediated autophagy in human hepatocellular carcinoma BEL-7402 cells
Li, T., Xu, X.-H., Tang, Z.-H., Wang, Y., Leung, C., Ma, D., Chen, X., Wang, Y., Chen, Y., & Lu, J. (2015) · Acta Pharmacologica Sinica · doi:10.1038/aps.2015.99 · Cited by 76 · see citing works
HMGB1-mediated autophagy attenuates gemcitabine-induced apoptosis in bladder cancer cells involving JNK and ERK activation
Yin, H., Yang, X., Gu, W., Liu, Y., Li, X., Huang, X., Zhu, X., Tao, Y., Gou, X., & He, W. (2017) · Oncotarget · doi:10.18632/oncotarget.17796 · Cited by 74 · see citing works
“This process releases Beclin-1 and leads to induction [39, 54].”
BackgroundSelf-citation
Neoalbaconol induces cell death through necroptosis by regulating RIPK-dependent autocrine TNFα and ROS production
Yu, X., Deng, Q., Li, W., Xiao, L., Luo, X., Liu, X., Yang, L., Peng, S., Ding, Z., Feng, T., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.3038 · Cited by 73 · see citing works
“Previous studies showed that triggering proteasomal degradation of cIAP1/2 could activate RIPK1 deubiquitination to induce cell death [12, 31].”
Killing colon cancer cells through PCD pathways by a novel hyaluronic acid-modified shell-core nanoparticle loaded with RIP3 in combination with chloroquine
Hou, X., Yang, C., Zhang, L., Hu, T., Sun, D., Cao, H., Yang, F., Guo, G. F., Gong, C., Zhang, X., et al. (2017) · Biomaterials · doi:10.1016/j.biomaterials.2016.12.032 · Cited by 74 · see citing works
Berberine as a potential agent for breast cancer therapy
Zhong, X.-D., Chen, L., Xu, X.-Y., Liu, Y., Tao, F., Zhu, M., Li, C., Zhao, D., Yang, G., & Chen, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.993775 · Cited by 70 · see citing works
Self-citation
Necroptosis: Molecular Signalling and Translational Implications
Giampietri, C., Starace, D., Petrungaro, S., Filippini, A., & Ziparo, E. (2014) · International Journal of Cell Biology · doi:10.1155/2014/490275 · Cited by 63 · see citing works
“…the recruitment of receptor-interacting protein 1 (RIP1) kinase and other proteins to form complex I. Subsequently, these proteins dissociate from TNFR1 and RIP1 can be found in the cytosol in complex IIb, which includes RIP1, receptor-interacting protein 3 (RIP3) kinase, caspase-8 and FADD.”
Background
Role of Bcl-xL/Beclin-1 in interplay between apoptosis and autophagy in oxaliplatin and bortezomib-induced cell death
Kim, S.-Y., Song, X., Zhang, L., Bartlett, D. L., & Lee, Y. J. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.027 · Cited by 64 · see citing works
“Previous studies have shown that Bcl-2/Bcl-xL phosphorylation may not only be a mechanism for regulating apoptosis and a mechanism for regulating autophagy, but perhaps also a mechanism for regulating the switch between the two pathways [31,42,43].”
Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells
Babcook, M. A., Sramkoski, R. M., Fujioka, H., Daneshgari, F., Almasan, A., Shukla, S., Nanavaty, R. R., & Gupta, S. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.500 · Cited by 61 · see citing works
The different roles of selective autophagic protein degradation in mammalian cells
Wang, D., Peng, Z.-J., Ren, G.-F., & Wang, G. (2015) · Oncotarget · doi:10.18632/oncotarget.5776 · Cited by 60 · see citing works
Migration and proliferation of cancer cells in culture are differentially affected by molecular size of modified citrus pectin
do Prado, S. B. R., Shiga, T. M., Harazono, Y., Hogan, V. A., Raz, A., Carpita, N. C., & Fabi, J. P. (2019) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2019.02.010 · Cited by 60 · see citing works
“Increased pERK levels are normally linked to cell migration and survival (Han, Khuri, & Roman, 2006; More, Chiplunkar, & Kalraiya, 2016; Xue & Hemmings, 2013), but pERK up-regulation can also induce cell necrosis by necroptosis or autophagy (He et al., 2013).”
Background
Relevance of necroptosis in cancer
Lalaoui, N., & Brumatti, G. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.120 · Cited by 56 · see citing works
Inhibiting of RIPK3 attenuates early brain injury following subarachnoid hemorrhage: Possibly through alleviating necroptosis
Chen, T., Pan, H., Li, J., Xu, H., Jin, H., Qian, C., Yan, F., Chen, J., Wang, C., Chen, J., et al. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.08.056 · Cited by 55 · see citing works
The inducible role of autophagy in cell death: emerging evidence and future perspectives
Huang, X., Yan, H., Xu, Z., Yang, B., Luo, P., & He, Q. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02135-w · Cited by 57 · see citing works
“…extensively induces the degradation of c-IAP1 and c-IAP2, the E3 ubiquitin ligases of RIPK1, thereby facilitating the formation of the ripoptosome (the complex of FADD, RIPK1, and Caspase-8 [84]), resulting in the activation of necrosomes and subsequent necrosis in A549 and UM-UC-3 cells [85] (Fig.”
Matrine induces RIP3-dependent necroptosis in cholangiocarcinoma cells
Xu, B., Xu, M., Tian, Y., Yu, Q., Zhao, Y., Chen, X., Mi, P., Cao, H., Zhang, B., Song, G., et al. (2017) · Cell Death Discovery · doi:10.1038/cddiscovery.2016.96 · Cited by 55 · see citing works
The interplay of autophagy and non-apoptotic cell death pathways
(2020) · International Review of Cell and Molecular Biology · doi:10.1016/bs.ircmb.2019.12.004 · Cited by 50 · see citing works
“…OPTN Negative Autophagosomal degradation of RIPK1 (Galluzzi et al., 2017a, Ito et al.,2016) cIAP1 Positive Autophagosomal degradation of cIAP1 (He et al., 2014) ATG5, PINK1, Drp1 Positive Mitophagy (Basit et al., 2017, Mizumura et al., 2014) Damaged Mitochondria, ROS Neutral Increased ROS due…”
Background
Effects of AQP5 gene silencing on proliferation, migration and apoptosis of human glioma cells through regulating EGFR/ERK/ p38 MAPK signaling pathway
Yang, J., Zhang, J., Chen, W., Wang, G., Mao, Q., Shan-quan, L., Xiong, W., Lin, Y., Ge, J., Li, X.-X., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.16461 · Cited by 49 · see citing works
“Proteins c-IAP1 and c-IAP2 directly inhibit the activity of Caspase-3, Caspase-7 and Caspase-9, thereby inhibiting cell apoptosis [41].”
BackgroundSelf-citation
RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells
Zheng, X., Yang, J., Wang, Y., Li, Q., Song, Y., Su, M., Li, J., Zhang, L., Li, Z., Zhou, B., et al. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-019-0340-7 · Cited by 46 · see citing works
Self-citation
Inhibition of kras-derived exosomes downregulates immunosuppressive BACH2/GATA-3 expression via RIP-3 dependent necroptosis and miR-146/miR-210 modulation
Petanidis, S., Domvri, K., Porpodis, Κ., Anestakis, D., Freitag, L., Hohenforst‐Schmidt, W., Tsavlis, D., & Zarogoulidis, P. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.109461 · Cited by 44 · see citing works
Epigenetic Regulation of RIP3 Suppresses Necroptosis and Increases Resistance to Chemotherapy in NonSmall Cell Lung Cancer
Wang, Q., Wang, P., Zhang, L., Tessema, M., Bai, L., Xu, X., Li, Q., Zheng, X., Saxton, B., Chen, W., et al. (2019) · Translational Oncology · doi:10.1016/j.tranon.2019.11.011 · Cited by 42 · see citing works
Self-citation
Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition
Wang, Q., Shi, S., He, W., Padilla, M. T., Zhang, L., Wang, X., Zhang, B., & Lin, Y. (2014) · Oncotarget · doi:10.18632/oncotarget.1798 · Cited by 40 · see citing works
“While RIP1 was reported to mediate cytotoxicity for anticancer drugs under some circumstances [30-32], a cytoprotective role for RIP1 is documented [15, 1719, 33].”
BackgroundSelf-citation
Role of the MAPK/cJun NH 2 -terminal kinase signaling pathway in starvation-induced autophagy
Barutcu, S., Girnius, N., Vernia, S., & Davis, R. J. (2018) · Autophagy · doi:10.1080/15548627.2018.1466013 · Cited by 40 · see citing works
“Subsequent studies have provided strong support for this role of MAPK8 in autophagy [6-19], although contributing roles for MAPK9 [20-23] and alternative potential functions of MAPK8 related to autophagy have also been reported [24-29].”
BackgroundResult
Taxifolin synergizes Andrographolide-induced cell death by attenuation of autophagy and augmentation of caspase dependent and independent cell death in HeLa cells
Alzaharna, M. M., Alqouqa, I., & Cheung, H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171325 · Cited by 39 · see citing works
Aging and uremia: Is there cellular and molecular crossover?
White, W. E. (2015) · World Journal of Nephrology · doi:10.5527/wjn.v4.i1.19 · Cited by 38 · see citing works
The Interplay Between Autophagy and Regulated Necrosis
Zhang, L., Cui, T., & Wang, X. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0110 · Cited by 37 · see citing works
Self-citation
Novel smac mimetic APG-1387 elicits ovarian cancer cell killing through TNF-alpha, Ripoptosome and autophagy mediated cell death pathway
Li, B. X., Wang, H. B., Qiu, M. Z., Luo, Q. Y., Han, Y., Yan, X., Pan, W. T., Lu, Y., Zhang, Y., Xu, J., et al. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0703-9 · Cited by 35 · see citing works
“In most cases, autophagy-associated death is accompanied with apoptosis [46].”
BackgroundSelf-citation
11-Methoxytabersonine Induces Necroptosis with Autophagy through AMPK/mTOR and JNK Pathways in Human Lung Cancer Cells
Ge, D., Tao, H., Fang, L., Kong, X., Han, L.-N., Li, N., Xu, Y., Li, L., Yu, M. Y., & Zhang, H. (2020) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.c19-00851 · Cited by 33 · see citing works
Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis
Shi, S., Wang, Q., Xu, J., Jang, J.-H., Padilla, M. T., Nyunoya, T., Xing, C., Zhang, L., & Lin, Y. (2015) · Oncotarget · doi:10.18632/oncotarget.2746 · Cited by 29 · see citing works
“We previously found that Chal-24 induces autophagy-dependent necroptosis at higher concentrations (8–32 μM) [17].”
BackgroundResultInfluentialSelf-citation
Preparation Of Nanobubbles Modified With A Small-Molecule CXCR4 Antagonist For Targeted Drug Delivery To Tumors And Enhanced Ultrasound Molecular Imaging
Peng, Y., Zhu, L., Wang, L., Liu, Y., Fang, K., Lan, M., Shen, D., Liu, D., Yu, Z., & Guo, Y. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s210478 · Cited by 29 · see citing works
Self-citation
Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like Cells
Chen, S.-M., Li, Y.-Y., Tu, C.-H., Salazar, N., Tseng, Y., Huang, S., Hsieh, L.-L., & Lui, T. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161299 · Cited by 27 · see citing works
Cytoplasmic and Nuclear Functions of cIAP1
Zadoroznyj, A., & Dubrez, L. (2022) · Biomolecules · doi:10.3390/biom12020322 · Cited by 25 · see citing works
Fentanyl induces autophagy via activation of the ROS/MAPK pathway and reduces the sensitivity of cisplatin in lung cancer cells
Yao, J., Ma, C., Gao, W., Liang, J., Liu, C., Yang, H., Yan, Q., & Wen, Q. (2016) · Oncology Reports · doi:10.3892/or.2016.5183 · Cited by 24 · see citing works
Activation of a c-Jun N-terminal kinase-mediated autophagy pathway attenuates the anticancer activity of gemcitabine in human bladder cancer cells
Huang, X., Zhang, H., Yang, X., Dong, X., Xie, X. S., Yin, H., Gou, X., Lin, Y., & He, W. (2017) · Anti-Cancer Drugs · doi:10.1097/cad.0000000000000499 · Cited by 24 · see citing works
Self-citation
Capsaicin Potentiates Anticancer Drug Efficacy Through Autophagy-Mediated Ribophorin II Downregulation and Necroptosis in Oral Squamous Cell Carcinoma Cells
Huang, Y., Yuan, T.-M., Liu, B., Liu, K., Wung, C.-H., & Chuang, S. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.676813 · Cited by 23 · see citing works
Death by over-eating: The Gaucher disease associated gene GBA1 , identified in a screen for mediators of autophagic cell death, is necessary for developmental cell death in Drosophila midgut
Dasari, S. K., Schejter, E. D., Bialik, S., Shkedy, A., Levin‐Salomon, V., Levin‐Zaidman, S., & Kimchi, A. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1380134 · Cited by 24 · see citing works
Suppression of JNK/ERK dependent autophagy enhances Jaspine B derivative-induced gastric cancer cell death via attenuation of p62/Keap1/Nrf2 pathways
Xu, F., Xie, Q., Li, Y., Jing, Q.-Q., Liu, X., Xu, Y., Wang, X., Liu, L., Kim, G., Choi, Y. H., et al. (2022) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2022.115908 · Cited by 22 · see citing works
Self-citation
Discovery of 2′-hydroxychalcones as autophagy inducer in A549 lung cancer cells
Wang, F.-W., Wang, S., Zhao, B., & Miao, J. (2014) · Organic & Biomolecular Chemistry · doi:10.1039/c3ob42429d · Cited by 22 · see citing works
The Multifaceted Effects of Autophagy on the Tumor Microenvironment
Kang, R., Zeh, H. J., Lotze, M. T., & Tang, D. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-35727-6_7 · Cited by 22 · see citing works
Autophagy‐Mediated Degradation of IAPs and c‐FLIPL Potentiates Apoptosis Induced by Combination of TRAIL and Chal‐24
Xu, J., Xu, X., Shi, S., Wang, Q., Saxton, B., He, W., Gou, X., Jang, J., Nyunoya, T., Wang, X., et al. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25397 · Cited by 21 · see citing works
“At high concentrations, (>4mM) Chal-24 activates autophagy-mediated necroptosis in cancer cells [He et al., 2014], but at lower concentrations ( 1mM), it potentiates cisplatin-induced apoptosis [Shi et al., 2015].”
BackgroundResultInfluentialSelf-citation
Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells
Zeng, Y., Tian, X., Wang, Q., He, W., Fan, J., & Gou, X. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s160557 · Cited by 20 · see citing works
“34,35 In the present study, ERK, but not the p38 and JNK pathways, was activated in RCC cells after RAD001 treatment, as well as the upregulation of downstream factors such as Beclin-1 and p-Bcl-2.”
Self-citation
The romantic history of signaling pathway discovery in cell death: an updated review
Wang, L., Liu, X., Li, Q.-Q., Zhu, Y., Ren, H.-L., Song, J., Zeng, J., Mei, J., Tian, H., Rong, D., et al. (2023) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04873-2 · Cited by 20 · see citing works
“It has been reported that chalcone derivative chalcone-24 killed the cancer cells by inducing autophagy and necroptosis [167].”
Hydroxysafflor yellow�A induces autophagy in human liver cancer cells by regulating Beclin�1 and ERK expression
Chen, Z., Liu, L., Liu, Y., Wang, S., Zhang, S., Dong, R., Xu, M., Ma, Y., Wang, J., Zhang, Q., et al. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8552 · Cited by 20 · see citing works
“He et al (33) reported that the use of a chalcone derivative, Chal‐24, induced autophagy and promoted cancer cell apoptosis, indicating that autophagic induction may serve as a novel treatment strategy for tumors.”
BackgroundSelf-citation
Induction of Apoptosis by Matrine Derivative ZS17 in Human Hepatocellular Carcinoma BEL-7402 and HepG2 Cells through ROS-JNK-P53 Signalling Pathway Activation
Wang, X., Zhang, S., Han, K., Wang, L., & Liu, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415991 · Cited by 19 · see citing works
Self-citation
The Emerging Role of Deubiquitinases in Cell Death
Zhou, Z., Song, X., Kang, R., & Tang, D. (2022) · Biomolecules · doi:10.3390/biom12121825 · Cited by 18 · see citing works
“Furthermore, USP27x is present in complex with BCL2L11 and BTRC, which facilitates BCL2L11 degradation in response to mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling and sensitizes human cancer cells to chemotherapeutic drugs [36].”
BackgroundInfluential
Recurring Amplification at 11q22.1-q22.2 Locus Plays an Important Role in Lymph Node Metastasis and Radioresistance in OSCC
Bhosale, P. G., Pandey, M., Cristea, S., Shah, M., Patil, A. J., Beerenwinkel, N., Schäffer, A. A., & Mahimkar, M. B. (2017) · Scientific Reports · doi:10.1038/s41598-017-16247-y · Cited by 18 · see citing works
Targeting regulated cell death (RCD) with naturally derived sesquiterpene lactones in cancer therapy
Xu, C., Wen, S., Du, X., Zou, X., Leung, E. L., Zhou, G., Wu, Q., & Shen, B. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107553 · Cited by 17 · see citing works
Unambiguous Identification of β‐Tubulin as the Direct Cellular Target Responsible for the Cytotoxicity of Chalcone by Photoaffinity Labeling
Zhou, B., Yu, X., Zhuang, C., Villalta, P. W., Lin, Y., Lü, J., & Xing, C. (2016) · ChemMedChem · doi:10.1002/cmdc.201600150 · Cited by 16 · see citing works
Self-citation
Novel synthetic chalcones induces apoptosis in human glioblastoma cells
Bittencourt, L. F. F., de Oliveira, K. A., Cardoso, C. B., Lopes, F. G., Dal-Cim, T. A., Chiaradia-Delatorre, L. D., Mascarello, A., Maluf, S. W., Yunes, R. A., Garcez, R. C., et al. (2016) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2016.03.022 · Cited by 15 · see citing works
A Comprehensive Review Highlighting the Prospects of Phytonutrient Berberine as an Anticancer Agent
Haque, S., Mathkor, D. M., Bhat, S. A., Musayev, A., Khituova, L., Ramniwas, S., Phillips, E., Swamy, N., Kumar, S., Yerer, M. B., et al. (2024) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.70073 · Cited by 14 · see citing works
“Notably, one study found that bioactive compounds curcumin and berberine can increase autophagic and apoptotic activities in several cancer cell lines via the ERK, N ‐ terminal kinase, and Beclin1/Bcl ‐ 2 signalling pathways [155, 156].”
Proteolytic control of regulated necrosis
Chico, J. F., Saggau, C., & Adam, D. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.05.025 · Cited by 14 · see citing works
Zinc finger protein 91 mediates necroptosis by initiating RIPK1-RIPK3-MLKL signal transduction in response to TNF receptor 1 ligation
zhong, Y., Zhang, Z. H., Wang, J. Y., Xing, Y., Ri, M., Jin, H. L., Zuo, H. X., Li, M. Y., Ma, J., & Jin, X. (2021) · Toxicology Letters · doi:10.1016/j.toxlet.2021.12.015 · Cited by 13 · see citing works
The SCFFBXO46 ubiquitin ligase complex mediates degradation of the tumor suppressor FBXO31 and thereby prevents premature cellular senescence
Choppara, S., Ganga, S., Manne, R., Dutta, P., Singh, S., & Santra, M. K. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005354 · Cited by 13 · see citing works
RNF167 ‐mediated ubiquitination of Tollip inhibits TNF‐α ‐triggered NF‐κB and MAPK activation
Yan, Z., Dai, J., Wang, J., Feng, Q., Wang, Y., Han, T., & Wu, C. (2023) · The FASEB Journal · doi:10.1096/fj.202201839r · Cited by 12 · see citing works
Exploiting Necroptosis for Therapy of Acute Lymphoblastic Leukemia
Mezzatesta, C., & Bornhauser, B. C. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00040 · Cited by 12 · see citing works
“Moreover, bypassing chemoresistance through autophagymediated necroptosis is possible upon chalcone treatment or using the tyrosine kinase inhibitor sorafenib (He et al., 2014; Kharaziha et al., 2015).”
Background
PSMC2 promotes resistance against temozolomide in glioblastoma via suppressing JNK-mediated autophagic cell death
Roy, P., Deepak, K., Das, C. K., Das, A., Biswas, A., Jena, B. C., & Mandal, M. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116755 · Cited by 11 · see citing works
New Frontiers in Cancer Chemotherapy — Targeting Cell Death Pathways
Xu, Y. Z., Kanagaratham, C., Youssef, M., & Radzioch, D. (2016) · InTech eBooks · doi:10.5772/61260 · Cited by 11 · see citing works
Autophagy and Tumor Cell Death
Cheng, Y., & Cao, L. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-4272-5_23 · Cited by 11 · see citing works
Receptor-interacting protein kinase 3 as a predictive adjuvant chemotherapy marker after lung adenocarcinoma resection
Chung, J. H., Yoon, S. H., Kang, Y. J., Kim, Y. S., Son, B. S., Kwon, R. J., Han, J., & Kim, D. H. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2018.12.65 · Cited by 10 · see citing works
Tea Polyphenol inhibits autophagy to sensitize Epirubicin-induced apoptosis in human bladder cancer cells
Gu, W., Lin, Y., Gou, X., & He, W. (2017) · Neoplasma · doi:10.4149/neo_2017_504 · Cited by 10 · see citing works
“As reported previously [22, 29, 30], JNK activation leads to phosphorylation or degradation of Bcl2, which suppress the Bcl-2/Beclin-1 complex to release the brake on Beclin-1-mediated autophagy activation.”
Self-citation
The “Dark Side” of autophagy on the maintenance of genome stability: Does it really exist during excessive activation?
Cheng, S. M., Shieh, M., Lin, T., & Cheung, C. H. A. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30555 · Cited by 9 · see citing works
Cx32 promotes autophagy and produces resistance to SN‑induced apoptosis via activation of AMPK signalling in cervical cancer
Fan, L.-X., Tao, L., Lai, Y., Cai, S., Zhao, Z., Yang, F., Su, R., & Wang, Q. (2021) · International Journal of Oncology · doi:10.3892/ijo.2021.5300 · Cited by 10 · see citing works
Self-citation
RIP1-Mediated Signaling Pathways in Cell Survival and Death Control
Lin, Y. (2014) · Springer eBooks · doi:10.1007/978-1-4614-8220-8_2 · Cited by 9 · see citing works
“Necroptosis could be a target for overcoming cancer’s chemoresistance (Kreuzaler and Watson 2012 ; He et al. 2013 ).”
BackgroundSelf-citation
Vasorin/ATIA Promotes Cigarette Smoke–Induced Transformation of Human Bronchial Epithelial Cells by Suppressing Autophagy-Mediated Apoptosis
Chen, W., Wang, Q., Xu, X., Saxton, B., Tessema, M., Leng, S., Choksi, S., Belinsky, S. A., Liu, Z.-G., & Lin, Y. (2019) · Translational Oncology · doi:10.1016/j.tranon.2019.09.001 · Cited by 9 · see citing works
Self-citation
Yunnan baiyao exerts anti-glioma activity by inducing autophagy-dependent necroptosis
Zhang, N., Guo, K., Lin, W., Wang, Z., Fuming, Z., Zhang, X., Zheng, D., & Ma, W. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118658 · Cited by 8 · see citing works
β-arrestin1 inhibits hypoxic injury-induced autophagy in human pulmonary artery endothelial cells via the Akt/mTOR signaling pathway
Ning, H., Deng, J., Chen, F., Liu, Y., Kong, D., Shan, L., Zhang, Z., & Hu, T. (2020) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2020.105791 · Cited by 8 · see citing works
Self-citation
Manipulating PP2Acα-ASK-JNK signaling to favor apoptotic over necroptotic hepatocyte fate reduces the extent of necrosis and fibrosis upon acute liver injury
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“Previous studies have indicated that JNK-dependent induction of reactive oxygen species (ROS) contributes to necroptosis induction [15] and have shown that PP2A can regulate TNF-α expression downstream of ASK1/JNK signaling [16].”
Background
Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy
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“However, the ability of autophagy to suppress necrotic death is considered one of its most important prosurvival mechanisms [48, 49], although other studies have shown that autophagy can promote necroptosis [50, 51].”
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Translational Research in Cancer
Sundaresan, S., & Gu, Y. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.73772 · Cited by 7 · see citing works
Exploration of the cytotoxic and microtubule disruption potential of novel imidazo[1,5- a ]pyridine-based chalcones
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Abstract 2277: Autophagy-associated necroptosis contributes to cancer cell cytotoxicity induced by the chalcone compound SBC2
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Autophagy‐Mediated Degradation of IAPs and c‐FLIPL Potentiates Apoptosis Induced by Combination of TRAIL and Chal‐24
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Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca2+-dependent mechanism
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Autophagy blockade sensitizes the anticancer activity of CA-4 via JNK-Bcl-2 pathway
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Autophagy as a mediator of chemotherapy-induced cell death in cancer
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Authors: He, W., Wang, Q., Srinivasan, B., Xu, J., Padilla, M. T., Li, Z., Wang, X., Liu, Y., Gou, X., Shen, H.-M., Xing, C., & Lin, Y.
Affiliations: Lovelace Respiratory Research Institute (US)
University of Minnesota (US)
Sichuan University (CN)
Chongqing Medical University (CN)
National University of Singapore (SG)
Corresponding author: Xing, C
Lin, Y
ORCID: He, W
Xu, J
Liu, Y
Gou, X
Xing, C
Lin, Y
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2013-07-08
Volume: 33
Issue: 23
Pages: 3004-3013
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/onc.2013.256
PMC: PMC3912228
OpenAlex: W2016036036
Cited by: 124
References: 46
Citations by year: 2026: 4 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 13 · 2018: 10 · 2017: 13 · 2016: 16 · 2015: 8 · 2014: 14 · 2013: 1
FWCI: 5.82
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R03CA156301)
National Institute of Environmental Health Sciences (R01ES017328)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords: JNK signaling, cIAP1, ripoptosome, RIPK1, RIPK3, Beclin-1, Bcl-2 phosphorylation, Bcl-xL, ERK signaling, chemoresistance, cancer chemotherapy, necrostatin-1
MeSH terms: Beclin-1, Autophagy-Related Protein 7, Baculoviral IAP Repeat-Containing 3 Protein, Antineoplastic Agents, Autophagy, Humans, Imidazoles, Indoles, Membrane Proteins, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Apoptosis, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Nuclear Pore Complex Proteins, RNA, Small Interfering, Ubiquitin-Activating Enzymes, Ubiquitin-Protein Ligases, Cell Line, Tumor, Chalcones, MAP Kinase Kinase 4, Apoptosis Regulatory Proteins, Inhibitor of Apoptosis Proteins, Receptor-Interacting Protein Serine-Threonine Kinases, Gene Knockdown Techniques

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A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy

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