TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

Zhang, Han; Chen, Zheng; Miranda, Roberto N.; Medeiros, L. Jeffrey; McCarty, Nami

doi:10.1158/0008-5472.can-16-0595

Cited by 48 publications

(43 citation statements)

References 49 publications

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“…The enhanced macroautophagy in turn, positively regulates TG2/NF-κΒ/IL-6 signaling, thereby implying a potential positive feedback loop required for cancer cell survival. Since increased TG2 levels are associated with poor prognosis in MCL patients, breaking TG2/NF-κΒ/IL-6/autophagy might be a potential therapeutic target for MCL 64 .…”

Section: Nf-κb Regulates Autophagy In Cancer Cellsmentioning

confidence: 99%

Life, death, and autophagy in cancer: NF-κB turns up everywhere

et al. 2020

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Escaping programmed cell death is a hallmark of cancer. NF-κB transcription factors are key regulator of cell survival and aberrant NF-κB signaling has been involved in the pathogenesis of most human malignancies. Although NF-κB is best known for its antiapoptotic role, other processes regulating the life/death balance, such as autophagy and necroptosis, seem to network with NF-κB. This review discusses how the reciprocal regulation of NF-κB, autophagy and programmed cell death affect cancer development and progression.

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Section: Nf-κb Regulates Autophagy In Cancer Cellsmentioning

confidence: 99%

Life, death, and autophagy in cancer: NF-κB turns up everywhere

et al. 2020

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“…In addition, autophagy has a positive feedback impact on IL‐6 and TG2 signaling to further stimulate this survival mechanism . TG2 knockdown leads to a reduction in autophagy and enhanced apoptosis . Use of the proteasome inhibitor, bortezomib, is an approved therapy for mantle cell lymphoma.…”

Section: Tg2 In Tumor Typesmentioning

confidence: 99%

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

Eckert

2019

Molecular Carcinogenesis

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Transglutaminase 2 (TG2) has emerged as a key cancer cell survival factor that drives epithelial to mesenchymal transition, angiogenesis, metastasis, inflammation, drug resistance, cancer stem cell survival and stemness, and invasion and migration. TG2 can exist in a GTP‐bound signaling‐active conformation or in a transamidase‐active conformation. The GTP bound conformation of TG2 contributes to cell survival and the transamidase conformation can contribute to cell survival or death. We present evidence suggesting that TG2 has a role in human cancer, summarize what is known about the TG2 mechanism of action in a range of cancer types, and discuss TG2 as a cancer therapy target.

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“…The significance of TG2 in many pathological processes has drawn much attention, and it has been proved that TG2 regulating many key proteins, including p65, p53 (37–39). To study its role in DNA repair, we performed an IP-MS analysis and found several potential interacting proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Transglutaminase 2 (TG2), a member of Transglutaminases family, exerts multiple physiological functions and is associated with cancer cell survival, metastatic behavior and chemoresistance (4–7). It has been proved that TG2 was related to multiple drug resistance including cisplatin, histone deacetylase inhibitor, EGFR-TKI etc (5, 8, 9).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting TG2 sensitizes lung cancer to radiotherapy through interfering TOPOIIα-mediated DNA repair

Xiao

Liu

Cao

et al. 2019

Preprint

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27Radiotherapy is an indispensable strategy for lung cancer, however, treatment failure 28 or reoccurrence is often found in patients due to the developing radioresistance. Novel 29 approaches are required for radiosensitizing to improve the therapeutic efficacy. In 30 present study, we found that transglutaminase 2 (TG2) confers radioresistance in 31 non-small cell lung cancer (NSCLC) cells through regulating TOPOIIα and promoting 32 DNA repair. Our data showed that TG2 inhibitor or knockdown increased NSCLC 33 radiosensitivity in vivo and in vitro. We found that TG2 translocated into nucleus and 34 located to DSB sites, surprisingly, knockdown TG2 or glucosamine inhibited the 35 phosphorylation of ATM, ATR and DNA-Pkcs. Through IP-MS assay and functional 36 experiments, we identified that TOPOIIα as an downstream factor of TG2. Moreover, 37we found that TGase domain account for the interaction with TOPOIIα. Finally, we 38 found that TG2 expression was correlated with poor survival in lung adenocarcinoma 39 instead of squamous cell carcinoma. In conclusion, we demonstrated that inhibiting 40 TG2 sensitize NSCLC to IR through interfere TOPOIIα mediated DNA repair, 41 suggesting TG2 as a potential radiosensitizing target in NSCLC. 42 43 65aberrant active in cancer cells (13)(14)(15). Previous study had showed that ATM inhibitor 66 KU55933 abrogated the constitutively activation of TG2 induced by genotoxic drug 67 MNNG (13). ATM mediated NF-kB activation increased the level of TG2. TG2 was 68 also proved as a target of p53 and involved in DNA damage repair, and knockdown of 69 p53 reduced the level of TG2 (14, 15). But the response of TG2 to ionizing radiation 70 and the exact role of TG2 in DNA repair remains to be uncovered. 71Here, we report that TG2 confers to radioresistance in NSCLC and enhanced 72 4 DNA repair capacity through directly interacting with DNA topoisomerase II α 73 (TOPOII α ). We found that ionizing radiation (IR) resulted in a rapid nuclear 74 translocation of TG2 and knockdown TG2 significantly inhibited DNA repair. TG2 75 was found to bind and activate TOPOIIα in nucleus to initial DNA damage repair 76 processes, such as phosphorylation of ATM, ATR and DNA-PKcs. Moreover, we used 77 a clinically used TG2 inhibitor, glucosamine, and found it significantly sensitized lung 78 cancer to IR in vivo and in vitro. Finally, we found TG2 was significantly correlated 79 with the survival in lung adenocarcinoma instead of squamous cell carcinoma patients, 80 which suggest possible prognostic value of TG2 in lung adenocarcinoma. These data 81 provide the possibility of clinical translation of TG2 inhibitor in the radiosensitization 82 of lung cancer. 83 84 5 Results 85 Inhibition of TG2 sensitizes lung cancer cells to ionizing radiation 86It has been proved that TG2 high expression was related to chemoresistance of 87 multiple cancers (16)(17)(18). To determine whether TG2 participates in radioresistance in 88 NSCLC, firstly we used a TG2 inhibitor, glucosamine, which was already used in 89 clinics as a...

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TG2 and NF-κB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy

Cited by 48 publications

References 49 publications

Life, death, and autophagy in cancer: NF-κB turns up everywhere

Life, death, and autophagy in cancer: NF-κB turns up everywhere

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

Inhibiting TG2 sensitizes lung cancer to radiotherapy through interfering TOPOIIα-mediated DNA repair

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