Targeting the Weak Point of Cancer by Induction of Necroptosis

Hu, Xun; Han, Weidong; Li, Ling

doi:10.4161/auto.4592

Cited by 59 publications

(50 citation statements)

References 18 publications

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“…In addition, programmed necrosis could be triggered to induce cell death in apoptotic/drug-resistant cancers against chemotherapy to counteract the 'Achilles heel' of cancers. 39 In this context, in solid tumors with acidic pHe, TRAIL may be an efficient inducer of necroptosis and the release of damageassociated molecular pattern molecules and proinflammatory cytokines may favor the recruitment of immune cells leading to tumor regression. In conclusion, our findings provide evidence that TRAIL-induced necroptosis involves RIPK1/ RIPK3-dependent PARP-1 activation.…”

Section: Discussionmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

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Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAILinduced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.

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Section: Discussionmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

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“…The concept of programmed necrosis was further validated by subsequent studies in which it was demonstrated that receptor-interacting protein 1 (RIP1, RIPK1) and receptor-interacting protein 3 (RIP3, RIPK3) act as initiators or effectors and necrostatin-1 (Nec-1) acts as an inhibitor of necrosis [24][25][26][27]. Although necrosis is controlled in a manner similar to apoptosis, this process involves distinct signaling pathways, and thus, the mechanisms that allow cancer cells to avoid apoptosis do not influence the activation of the necrotic pathway [28].…”

Section: Introductionmentioning

confidence: 98%

Lycorine induces programmed necrosis in the multiple myeloma cell line ARH-77

et al. 2014

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Lycorine, a natural alkaloid, has been widely reported to possess potential efficacy against cancer. However, the anti-multiple myeloma mechanism of lycorine is not fully understood. In this study, the results demonstrated that lycorine is effective against multiple myeloma cell line ARH-77 via inducing programmed necrosis. The mechanisms of lycorine on the multiple myeloma cell line ARH-77 are associated with G1 phase cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, ATP depletion, and DNA damage. Our results elucidate the new mechanism of lycorine against multiple myeloma.

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“…Murine tumor models provide means to study the biology of heterogeneous cancer cell populations in tumors arising as a consequence of well-defined genetic mutations in an immunocompetent microenvironment. There are currently several genetic murine models of ovarian cancer, which utilize ovarian bursal injection of an adenovirus expressing Cre recombinase (AdCre) to induce Cre-mediated deletion of specific tumor suppressor genes in the OSE (12–14). Wu et al developed a model of a high-grade endometrioid ovarian carcinoma, which develops after inactivation of Apc , Pten, Trp53 .…”

Section: Introductionmentioning

confidence: 99%

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

Burgos-Ojeda

McLean

et al. 2015

Molecular Cancer Therapeutics

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Ovarian cancer is known to be composed of distinct populations of cancer cells, some of which demonstrate increased capacity for cancer initiation and/or metastasis. The study of human cancer cell populations is difficult due to long requirements for tumor growth, inter-patient variability and the need for tumor growth in immune-deficient mice. We therefore characterized the cancer initiation capacity of distinct cancer cell populations in a transgenic murine model of ovarian cancer. In this model, conditional deletion of Apc, Pten, and Trp53 in the ovarian surface epithelium (OSE) results in the generation of high grade metastatic ovarian carcinomas. Cell lines derived from these murine tumors express numerous putative stem cell markers including CD24, CD44, CD90, CD117, CD133 and ALDH. We show that CD24+ and CD133+ cells have increased tumor sphere forming capacity. CD133+ cells demonstrated a trend for increased tumor initiation while CD24+ cells vs CD24− cells, had significantly greater tumor initiation and tumor growth capacity. No preferential tumor initiating or growth capacity was observed for CD44+, CD90+, CD117+, or ALDH+ versus their negative counterparts. We have found that CD24+ cells, compared to CD24− cells, have increased phosphorylation of STAT3 and increased expression of STAT3 target Nanog and c-myc. JAK2 inhibition of STAT3 phosphorylation preferentially induced cytotoxicity in CD24+ cells. In vivo JAK2 inhibitor therapy dramatically reduced tumor metastases, and prolonged overall survival. These findings indicate that CD24+ cells play a role in tumor migration and metastasis and support JAK2 as a therapeutic target in ovarian cancer.

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Targeting the Weak Point of Cancer by Induction of Necroptosis

Cited by 59 publications

References 18 publications

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

Lycorine induces programmed necrosis in the multiple myeloma cell line ARH-77

CD24+ Ovarian Cancer Cells Are Enriched for Cancer-Initiating Cells and Dependent on JAK2 Signaling for Growth and Metastasis

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