The NQO1/PKLR axis promotes lymph node metastasis and breast cancer progression by modulating glycolytic reprogramming

Yang, Yang; Zhu, Guang; Dong, Bing; Piao, Jinhua; Lin, Zhenhua

doi:10.1016/j.canlet.2019.03.054

Cited by 40 publications

(29 citation statements)

References 45 publications

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“…Based on the existing studies, the suppressive roles of RKIP on transcription factors, like STAT3 27,31 , YY1 26 , and NF-κB 25 , may involve the regulation of miR-450b-5p in NPC, which needs to be validated in the future work. As a phase II antioxidant enzyme, NQO1, being regulated by NRF2, is aberrantly upregulated in multiple cancers such as pancreatic cancer 52 , glioblastoma 53 , lung cancer 54 , and breast cancer 55 , and contributes a lot to therapy resistance, especially for radioresistance. β-lapachone, an NQO1-targeting prodrug, are potent to selectively sensitize cancer cells to radiation by aggravating the degree of ROS stress and evoking cell apoptosis in cancers with upregulation of NQO1, including head and neck cancer 56 and non-small cell lung cancer 54 .…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

et al. 2020

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Dysregulation of RKIP and NRF2 has been widely involved in the therapy resistance of multiple malignances, however, their relation and the corresponding mechanisms, especially in radiation response, have not been elucidated. In this study, we revealed that RKIP could negatively regulate the expression of NRF2 in nasopharyngeal carcinoma (NPC) cells. Depletion or ectopic expression of NRF2 countered the pro- or anti- radioresistant effects of RKIP knockdown or overexpression on NPC cells, respectively, both in vitro and in vivo. Furthermore, our results indicated that NQO1 was positively regulated by NRF2 and served as the downstream effector of RKIP/NRF2 axis in regulation of NPC radioresistance. Mechanistically, miR-450b-5p, being positively regulated by RKIP in NPC cells, could sensitize NPC cells to irradiation by directly targeting and suppressing the level of NRF2. Besides, we analyzed the level of aforementioned molecules in NPC tissues. The results indicated that RKIP was significantly downregulated, NRF2 and NQO1 were notably upregulated in NPC tissues compared with in normal nasopharyngeal mucosa (NNM) tissues. Furthermore, RKIP and miR-450b-5p were remarkably lower, yet NRF2 and NQO1 were notably higher, in radioresistant NPC tissues relative to in radiosensitive NPC tissues. Consistent with the pattern in NPC cells, the RKIP/miR-450b-5p/NRF2/NQO1 axis was significantly correlated in NPC tissues. Downregulation of RKIP and miR-450b-5p, and upregulation of NRF2 and NQO1, positively correlated to malignant pathological parameters such as primary T stage, Lymph node (N) metastasis, and TNM stage. Finally, RKIP and miR-450b-5p served as favorable prognostic indicators, and NRF2 and NQO1 acted as unfavorable prognostic biomarkers in patients with NPC. Collectively, our outcomes reveal that RKIP downregulation promotes radioresistance of NPC by downregulating miR-450b-5p and subsequently upregulating and activating NRF2 and NQO1, highlighting RKIP/miR-450b-5p/NRF2/NQO1 axis as a potential therapeutic target for improving the radiosensitivity of NPC.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

et al. 2020

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“…A mitochondria-targeted LND demonstrated an antimetastatic effect in vitro and in vivo by inhibition of bioenergetics, induction of ROS and inactivation of AKT/mTOR/p70S6K signaling. Glycolysis blockade with 2- DG or 3-BrPA reversed NAD(P)H:quinone oxidoreductase-1 (NQO1)-induced EMT by inhibiting vimentin, Snail, Slug and Twist, and up-regulating E-cadherin, leading to attenuated NQO1-induced glycolysis and metastasis in breast cancer cells [ 111 ]. Lonidamine and 2-DG are currently in Phase I-III clinical trials of multiple metastatic cancers [ 112 – 114 ].…”

Section: Metastatic Signaling-mediated Regulation Of Metabolic Gene Ementioning

confidence: 99%

“…2-DG abrogates NQO1/PKLRdependent glycolysis and tumor metastasis by reversing EMT. Lonidamine (Phase II/III); 2-deoxyglucose (Phase I/II) NCT00435448 NCT00096707 NCT00188929 [ 111 , 146 , 147 ] 3-Bromopyruvate (3-BrPA) GAPDH 3-BrPA inhibits GAPDH, acetyl-CoA production and attenuates NQ01/ PKLR signaling axis-enhanced tumor glycolysis and metastasis via EMT. N.A.…”

Section: Metastatic Signaling-mediated Regulation Of Metabolic Gene Ementioning

confidence: 99%

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

et al. 2020

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Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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“…The overexpression of NQO1 in lung, gastric, colon, cervical, pancreatic and breast cancer is closely associated with poor patient prognosis [13]. As a regulator of transcription factor NRF2, the increased expression of NQO1 in cancer cells contributes to tolerance to oxidative stress [9].…”

Section: Discussionmentioning

confidence: 99%

Expression of NAD(P)H:Quinone Oxidoreductase 1 and Its Significance in Human Abdominal Aortic Aneurysmal Tissues

Zhang

Zhao

Xiong

et al. 2020

Preprint

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Background NAD(P)H:quinone oxidoreductase 1 (NQO1) protein protects cells against redox cycling of quinones and oxidative stress. Oxidative stress represents key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NQO1 in AAA formation has not been investigated previously.Methods The Tandem Mass Tag (TMT) labeling quantitative proteomics technique was utilized to detect 3 AAA tissues and 3 corresponding adjacent normal abdominal aorta tissue specimens. Immunohistochemistry was used to detect NQO1 expression in 8 AAA tissues, and the correlation with AAA size, MDA and SOD levels was analyzed. The senescence model of human vascular smooth muscle cell (VSMCs) induced by Angiotensin II (AngII) was established in vitro. The effect of AngII on the level of reactive oxygen species (ROS) and β-galactosidase activity of VSMCs were observed after NQO1 expression was inhibited by specific interfering RNA (si-NQO1) technique.Results NQO1 expression was the highest up-regulation (3.1fold) among 11 differentially expressed oxidative stress-related proteins (> 1.2 or<0.83 and P<0.05), and the expression of NQO1 was positively correlated with the AAA size (R2=0.517, P<0.05) and MDA level (R2=0.659, P<0.05). AngII treatment of human VSMCs increased ROS expression and β-galactosidase activity, while knocking down NQO1 expression promoted AngII-induced ROS production and cell aging. Conclusion Up-regulation of NQO1expression plays an antioxidant role in AAA, and it is expected to be a biomarker for early diagnosis and prognosis assessment of AAA.

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The NQO1/PKLR axis promotes lymph node metastasis and breast cancer progression by modulating glycolytic reprogramming

Cited by 40 publications

References 45 publications

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

RETRACTED ARTICLE: Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Expression of NAD(P)H:Quinone Oxidoreductase 1 and Its Significance in Human Abdominal Aortic Aneurysmal Tissues

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