NLRC3 inhibits MCT‐induced pulmonary hypertension in rats via attenuating PI3K activation

Zha, Lihuang; Zhou, Jun; Li, Tangzhiming; Luo, Hui; Zhang, Men‐qiu; Sheng, Li; Yu, Zaixin

doi:10.1002/jcp.28255

Cited by 21 publications

(19 citation statements)

References 43 publications

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“…Saline was given to the control group as placebo. For the other four groups, MCT (60 mg/kg) [24,25] was injected into the subcutaneous tissue to induce progressive pulmonary arterial hypertension at the end of 21 days.…”

Section: Methodsmentioning

confidence: 99%

Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

Feng

et al. 2020

Oxidative Medicine and Cellular Longevity

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Pulmonary arterial hypertension (PAH) is a lethal disease generally characterized by pulmonary artery remodeling. Mitochondrial metabolic disorders have been implicated as a critical regulator of excessively proliferative- and apoptosis-resistant phenotypes in pulmonary artery smooth muscle cells (PASMCs). Dichloroacetate (DCA) is an emerging drug that targets aerobic glycolysis in tumor cells. Atorvastatin (ATO) is widely used for hyperlipemia in various cardiovascular diseases. Considering that DCA and ATO regulate glucose and lipid metabolism, respectively, we hypothesized that the combination of DCA and ATO could be a potential treatment for PAH. A notable decrease in the right ventricular systolic pressure accompanied by reduced right heart hypertrophy was observed in the DCA/ATO combination treatment group compared with the monocrotaline treatment group. The DCA/ATO combination treatment alleviated vascular remodeling, thereby suppressing excessive PASMC proliferation and macrophage infiltration. In vitro, both DCA and ATO alone reduced PASMC viability by upregulating oxidative stress and lowering mitochondrial membrane potential. Surprisingly, when combined, DCA/ATO was able to decrease the levels of reactive oxygen species and cell apoptosis without compromising PASMC proliferation. Furthermore, suppression of the p38 pathway through the specific inhibitor SB203580 attenuated cell death and oxidative stress at a level consistent with that of DCA/ATO combination treatment. These observations suggested a complementary effect of DCA and ATO on rescuing PASMCs from a PAH phenotype through p38 activation via the regulation of mitochondrial-related cell death and oxidative stress. DCA in combination with ATO may represent a novel therapeutic strategy for PAH treatment.

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Section: Methodsmentioning

confidence: 99%

Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

Feng

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…14 Zha et al revealed that NLRC3 protected against monocrotaline (MCT)-induced rat pulmonary hypertension (PH) and platelet-derived growth factor-BB (PDGF-BB)induced PASMCs proliferation, migration, and inflammation through a mechanism involving PI3K inhibition. 15 Of note, recent studies have focused on the function of NLRC3 in carcinogenesis and tumor development. 9,10 However, the expression of NLRC3 in bladder cancer tissues and its potential clinical and biological significances have not been described.…”

Section: Discussionmentioning

confidence: 99%

miR‐190b promotes tumor growth and metastasis via suppressing NLRC3 in bladder carcinoma

et al. 2020

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Bladder cancer is one of the most common urogenital malignancies. However, its pathogenesis, especially molecular mechanisms remain elusive. Thus, understanding the molecular mechanisms underlying bladder cancer is important for the discovery of novel therapeutic paradigms for these diseases. In current study, we found that micro‐RNA (miR)‐190b is highly expressed in bladder cancer tissues and cells. Overexpression of miR‐190b enhanced the proliferation, growth, migration and invasion capabilities, and angiogenesis of bladder cancer cells, whereas downregulation of miR‐190b reversed these effects. Target prediction and dual luciferase reporter assays identified NLR family CARD domain containing 3 (NLRC3) as a potential target of miR‐190b. Pathway analysis indicated that miR‐190b promotes bladder cancer progression via the Wnt/β‐catenin and mTOR signaling pathways. Taken together, our findings imply that miR‐190b acts as a critical regulator for bladder cancer development by repressing NLRC3 and partly through the Wnt/β‐catenin and mTOR pathways. Our study suggests that miR‐190b may be served as a potential therapeutic target for bladder cancer treatment.

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“…NLRC3/PI3K pathway is a newly discovered intriguing signaling pathway that has been reported to mediate cell survival in multiple cancer types. 32,33 Initial studies have shown that NLRC3 is primarily involved in innate immune responses. Moreover, it has been confirmed to alleviate nonspecific immune responses during virus infection.…”

Section: Discussionmentioning

confidence: 99%

“…Microarray data and bioinformatics analysis showed that NLRC3 and AKT signaling pathway might be key downstream mediators. NLRC3/PI3K pathway is a newly discovered intriguing signaling pathway that has been reported to mediate cell survival in multiple cancer types 32,33 . Initial studies have shown that NLRC3 is primarily involved in innate immune responses.…”

Section: Discussionmentioning

confidence: 99%

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

Pan

Liu

Wang

et al. 2020

Molecular Carcinogenesis

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Dihydromethysticin (DHM), a natural compound derived from Kava, has been reported to be effective against mental disorders and some malignant tu mors. However, little is known about the inhibitory effect of DHM on colorectal cancer (CRC). First, we examined the impact of DHM on human colon cancer cell lines, which demonstrated that DHM inhibits proliferation, migration, and invasion and promotes apoptosis and cell cycle arrest in colon cancer cells in vitro. Using small hairpin RNA, we inhibited nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3)/phosphoinositide 3-kinase (PI3K) pathway to elucidate the partial signaling of DHM-mediated tumor suppression. Additionally, using an ectopic human CRC model, we verified whether DHM inhibits tumor growth and angiogenesis via the NLRC3/PI3K pathway in vivo. Overall, DHM showed an inhibitory effect on CRC by altering cell proliferation, migration, invasion, apoptosis, cell cycle, and angiogenesis, possibly via the NLRC3/PI3K pathway. Thus, DHM may be a promising candidate for CRC therapy. K E Y W O R D S colorectal cancer, dihydromethysticin, NLRC3 1 | INTRODUCTION Colorectal cancer (CRC) is third most prevailing malignant tumor in the world. In 2016, approximately 134 490 individuals were diagnosed with CRC in the United States, and it was responsible for mortality of more than one-third. 1 In the past few decades, remarkable progress has been made in the treatment of CRC with variety of chemotherapy drugs and immunotherapies constantly emerging. However, due to drug resistance and dose-limiting toxicity, limited success has been achieved in treating advanced CRC. 2 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CDK4, cyclin-dependent kinase 4; CK, creatine kinase.; CRC, colorectal cancer; DAPI, 4′, 6-diamidino-2-phenylindole; DHM, dihydromethysticin; H&E staining, hematoxylin and eosin staining; JNK, c-Jun NH2 terminal kinase; LDH, lactate dehydrogenase; MMP2, matrix metallopeptidase 2; MMP9, matrix metallopeptidase 9; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; NLRC3, nucleotide-oligomerization domain-like receptor subfamily C3; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; RIPA, radio immunoprecipitation assay; TUNEL, terminal dUTP nick-end labeling; VEGF, vascular endothelial growth factor. Huayang Pan, Fukai Liu, and Jinge Wang contributed equally to this work. Terminal dUTP nick-end labeling (TUNEL) assay was performed according to the manufacturer's instructions (Roche, Shanghai, China). CRC cells were washed once with PBS, fixed with formalin for 30 minutes, and washed again with PBS. Cells were then suspended 576 | PAN ET AL.

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NLRC3 inhibits MCT‐induced pulmonary hypertension in rats via attenuating PI3K activation

Cited by 21 publications

References 43 publications

Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

miR‐190b promotes tumor growth and metastasis via suppressing NLRC3 in bladder carcinoma

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway

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