Ye Ma

Southern Medical University

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Xuegang Sun

Shanghai University of Traditional Chinese Medicine

Chunhui Chen

Beijing Normal University

Qinrui Han

Southern Medical University

Yihua Xu

Zhejiang University

Ruibo Sun

State Administration of Traditional Chinese Medicine of the People's Republic of China

Liyi Wu

State Administration of Traditional Chinese Medicine of the People's Republic of China

Linlin Jing

TCM-Intigrated Cancer Center of Southern Medical University

Yu Dai

Shenzhen Maternity and Child Healthcare Hospital

Wanyu Yao

State Administration of Traditional Chinese Medicine of the People's Republic of China

Qingyuan Zhang

Harbin Medical University

Cooperative Institutions

Southern Medical University

State Administration of Traditional Chinese Medicine of the People's Republic of China

Nanfang Hospital

Guangdong Academy of Medical Sciences

Guangdong Provincial People's Hospital

Guangdong General Hospital

The First People's Hospital of Shunde

Huazhong University of Science and Technology

University of Chinese Academy of Sciences

Guangzhou Medical University

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Autophagic flux is essential for the downregulation of D-dopachrome tautomerase by atractylenolide I to ameliorate intestinal adenoma formation

Journal of Cell Communication and Signaling (2018)

Lu Li Linlin Jing Junjiang Wang Xu Wenjuan Xianling Gong

Adenomatous polyposis coli

10.1007/s12079-018-0454-6

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Citations (8)

Sirt3 restricts tumor initiation via promoting LONP1 deacetylation and K63 ubiquitination

Journal of Translational Medicine (2023)

Liyi Wu Xinyi Yan Ruibo Sun Ye Ma Wanyu Yao

Abstract Background Sirtuin 3 (Sirt3) is a controversial regulator of carcinogenesis. It residents in the mitochondria and gradually decays during aging. In this study, we tried to investigate the role of Sirt3 in carcinogenesis and to explore its involvement in metabolic alteration. Methods We generated conditional intestinal epithelium Sirt3-knockout mice by crossing Apc Min/ + ; Villin-Cre with Sirt3 fl/fl (AVS) mice. The deacetylation site of Lon protease-1 (LONP1) was identified with Mass spectrometry. The metabolic flux phenotype was determined by Seahorse bioanalyzer. Results We found that intestinal epithelial cell-specific ablation of Sirt3 promotes primary tumor growth via stabilizing mitochondrial LONP1. Notably, we newly identified that Sirt3 deacetylates human oncogene LONP1 at N terminal residue lysine 145 (K145). The LONP1 hyperacetylation-mutant K145Q enhances oxidative phosphorylation to accelerate tumor growth, whereas the deacetylation-mutant K145R produces calorie-restriction like phenotype to restrain tumorigenesis. Sirt3 deacetylates LONP1 at K145 and subsequently facilitates the ESCRT0 complex sorting and K63-ubiquitination that resulted in the degradation of LONP1. Our results sustain the notion that Sirt3 is a tumor-suppressor to maintain the appropriate ubiquitination and degradation of oncogene LONP1. Conclusion Sirt3 represents a targetable metabolic checkpoint of oncogenesis, which produces energy restriction effects via maintaining LONP1 K145 deacetylation and subsequent K63 ubiquitination.

SIRT3

10.1186/s12967-023-03925-x

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Citations (9)

DFB Suppresses Obesity-Driven CRC Via Restricting Progenitor to Terminally Exhausted T Cell Differentiation

Research Square (Research Square) (2021)

Yihua Xu Hao Wang Tao Wang Chunhui Chen Wanyu Yao

Abstract Background: Obesity contributes to about 30% incidence of colorectal cancer (CRC). Obese tumor microenvironment compromises anti-tumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang Decoction (DFB), a combined classical prescription from “Synopsis of Golden Chamber”, modulates the differentiation of tumor-infiltrating CD8 + T cells Methods: Our present study was to use transgenic ob/ob mice to examine the effects of DFB and to explore its novel mechanism on modulating the differentiation of tumor-infiltrating CD8 + T cells. Results: DFB regresses tumor growth in high-fat diet induced obese mice via expanding PD-1 int TIM3 - and restricting PD-1 hi TIM3 + subset. TCF1 is highly expressed in PD-1 int TIM3 - subset but is absent in PD-1 hi TIM3 + cells. We next confirm that progenitor PD-1 int TCF + cells robustly produce TNFɑ and IFNγ while terminally differentiated PD-1 int TCF + cells have defects in generating TNFɑ. With transgenic ob/ob mice, we find that DFB produces cooperative efficacy with anti-PD-1 (ɑPD-1) by limiting PD-1 hi Tim3 + subset and amplifying PD-1 int TCF + population. Finally, we identify that the differentiation from progenitor to terminal Tex is driven, at least in part, by CCL2. CCR2 inhibitor enhances the response to ɑPD-1 by promoting the counts of progenitor Tex. Conclusion: Altogether, DFB dampens CCL2 and preserves progenitor Tex in obese microenvironment to restrain CRC progression. These finds provide unambiguous evidence that traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and give rise to strong rationale for further clinical verification.

Progenitor

10.21203/rs.3.rs-952538/v1

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Resibufogenin suppresses colorectal cancer growth and metastasis through RIP3-mediated necroptosis

Journal of Translational Medicine (2018)

Qinrui Han Ye Ma Hao Wang Yu Dai Chunhui Chen

Necroptotic susceptibility is probably an intrinsic weakness of cancer. Here, we report that resibufogenin, a member of bufadienolide family, suppresses the growth and metastasis of colorectal cancer (CRC) through induction of necroptosis in vivo. SW480 cells with stably expressing enhanced green fluorescence protein were xenografted to BALB/c-nu mice to observe the growth of tumors. Liver metastasis was observed by injection of MC38 cells beneath the splenic capsule of mice. Protein expression was determined by immunohistochemistry, immunofluorescence and western blot. Consolidated in vitro results indicate that resibufogenin has anti-proliferative activity on CRC cells. PI staining and transmission electron microscope imaging suggest that the cell death induced by resibufogenin are mainly through necrosis, which is further confirmed by the ineffectiveness of z-VAD, a pan-caspase general inhibitor. In particular, resibufogenin induced necrosis is substantially abrogated in receptor-interacting protein kinase 3 (RIPK3) knockout mouse embryo fibroblasts. The RIP3-dependent necrosis has been classified as necroptosis. Resibufogenin triggeres necroptosis through upregulating RIP3 and phosphorylating mixed lineage kinase domain-like protein at Ser358. Resibufogenin also activates the expression of PYGL, GLUD1 and GLUL in a RIP3-dependent manner. Resibufogenin exerts cytotoxic effect by inducing reactive oxygen species accumulation which can be neutralized by N-acetylcysteine. Remarkably, resibufogenin significantly suppresses liver-metastasis from spleen implantation. The anti-neoplastic effect of this compound can be abrogated by RIP3 knockdown. Resibufogenin suppresses growth and metastasis of CRC through RIP3-mediated necroptosis.

RIPK1

10.1186/s12967-018-1580-x

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Citations (104)

PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting

Autophagy (2024)

Qingyuan Zhang Chunhui Chen Ye Ma Xinyi Yan Nianhong Lai

Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.

Cancer Cachexia

Protein Degradation

10.1080/15548627.2024.2360340

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Citations (5)

Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia‐inducible factor 1α axis

Cancer Science (2019)

Xiaowu Li Chunhui Chen Yu Dai Chengzhi Huang Qinrui Han

Inducing angiogenesis is a hallmark of cancers that sustains tumor growth and metastasis. Neovascularization is a surprisingly early event during the multistage progression of cancer. Cinobufagin, an important bufadienolide originating from Chan Su, has been clinically used to treat cancer in China since the Tang dynasty. Here, we show that cinobufagin suppresses colorectal cancer ( CRC ) growth in vivo by downregulating angiogenesis. The hierarchized neovasculature is significantly decreased and the vascular network formation is disrupted in HUVEC by cinobufagin in a dose‐dependent way. Endothelial apoptosis is observed by inducing reactive oxygen species ( ROS ) accumulation and mitochondrial dysfunction which can be neutralized by N‐acetyl‐ l ‐cysteine ( NAC ). Expression of hypoxia‐inducible factor 1α ( HIF ‐1α) is reduced and phosphorylation of mTOR at Ser2481 and Akt at Ser473 is downregulated in HUVEC . Endothelial apoptosis is triggered by cinobufagin by stimulation of Bax and cascade activation of caspase 9 and caspase 3. Increased endothelial apoptosis rate and alterations in the HIF ‐1α/ mTOR pathway are recapitulated in tumor‐bearing mice in vivo. Further, the anti‐angiogenesis function of cinobufagin is consolidated based on its pro‐apoptotic effects on an EOMA ‐derived hemangioendothelioma model. In conclusion, cinobufagin suppresses tumor neovascularization by disrupting the endothelial mTOR / HIF ‐1α pathway to trigger ROS ‐mediated vascular endothelial cell apoptosis. Cinobufagin is a promising natural anti‐angiogenetic drug that has clinical translation potential and practical application value.

10.1111/cas.13988

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Citations (34)

Modified Shenlingbaizhu Decoction represses the pluripotency of colorectal cancer stem cells by inhibiting TGF-β mediated EMT program

Phytomedicine (2022)

Yu Dai Hao Wang Ruibo Sun Jianxin Diao Ye Ma

10.1016/j.phymed.2022.154234

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Citations (12)

Dahuang Fuzi Baijiang decoction restricts progenitor to terminally exhausted T cell differentiation in colorectal cancer

Cancer Science (2022)

Yihua Xu Hao Wang Tao Wang Chunhui Chen Ruibo Sun

Abstract Obesity increases the risk of colorectal cancer (CRC) by 30%. The obese tumor microenvironment compromises antitumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang decoction (DFB) is a combined classical prescription from the “Synopsis of Prescriptions of the Golden Chamber”. We first determined that DFB regresses tumor growth in high‐fat diet–induced obese mice by expanding the TIM3 − subset with intermediate expression of programmed cell death‐1 (PD‐1 int TIM 3− ) and restricting the PD‐1 hi TIM3 + subset. Transcription factor 1 (TCF1) is highly expressed in the PD‐1 int TIM3 − subset but is absent in PD‐1 hi TIM3 + cells. We next confirmed that progenitor PD‐1 int TCF + cells robustly produce tumor necrosis factor‐α (TNFα) and interferon‐γ, whereas terminally differentiated PD‐1 int TCF + cells have defects in generating TNFα. With transgenic ob / ob mice, we found that DFB produces cooperative efficacy with anti‐PD‐1 (αPD‐1) by limiting the PD‐1 hi Tim3 + subset and amplifying the PD‐1 int TCF + population. Finally, we defined the recombinant chemokine C‐C‐motif receptor 2 (CCR2) + CD8 + subset as terminal Tex and identified that the differentiation from progenitor to terminal Tex is driven, at least in part, by the chemokine (C‐C motif) ligand 2 (CCL2)/CCR2 axis. The CCR2 inhibitor enhances the response to αPD‐1 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in the obese microenvironment to restrain CRC progression. These findings provide unambiguous evidence that the traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and establish a strong rationale for further clinical verification.

CCR2

Progenitor

10.1111/cas.15311

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Citations (14)