Activin A is a prominent autocrine regulator of hepatocyte growth arrest

Haridoss, Srividyameena; Yovchev, Mladen I.; Schweizer, Hannah; Megherhi, Sabreen; Beecher, Maria; Locker, Joseph; Oertel, Michael

doi:10.1002/hep4.1106

Cited by 19 publications

(23 citation statements)

References 49 publications

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“…These observations indicate that activin A may represent a key element in TGFb signaling-mediated paracrine senescence. This hypothesis is supported by the proposed use of activin A as a potential blood biomarker for senescent cell burden in vivo (44), and is consistent with the recently published role of activin A as a prominent autocrine regulator of hepatocyte growth arrest and cellular senescence through CDKN2B/p15 ink4a (45).…”

Section: Discussionsupporting

confidence: 87%

Oncogene-Induced Senescence Limits the Progression of Pancreatic Neoplasia through Production of Activin A

Zhao

Chanal

et al. 2020

Cancer Research

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Pancreatic ductal adenocarcinoma (PDAC) is a deadly and aggressive cancer. Understanding mechanisms that drive preneoplastic pancreatic lesions is necessary to improve early diagnostic and therapeutic strategies. Mutations and inactivation of activinlike kinase (ALK4) have been demonstrated to favor PDAC onset. Surprisingly, little is known regarding the ligands that drive ALK4 signaling in pancreatic cancer or how this signaling pathway limits the initiation of neoplastic lesions. In this study, data mining and histologic analyses performed on human and mouse tumor tissues revealed that activin A is the major ALK4 ligand that drives PDAC initiation. Activin A, which is absent in normal acinar cells, was strongly induced during acinar-to-ductal metaplasia (ADM), which was promoted by pancreatitis or the activation of Kras G12D in mice. Activin A expression during ADM was associated with the cellular senescence program that is induced in precursor lesions. Blocking activin A signaling through the use of a soluble form of activin receptor IIB (sActRIIB-Fc) and ALK4 knockout in mice expressing Kras G12D resulted in reduced senescence associated with decreased expression of p21, reduced phosphorylation of H2A histone family member X (H2AX), and increased proliferation. Thus, this study indicates that activin A acts as a protective senescence-associated secretory phenotype factor produced by Kras-induced senescent cells during ADM, which limits the expansion and proliferation of pancreatic neoplastic lesions.Significance: This study identifies activin A to be a beneficial, senescence-secreted factor induced in pancreatic preneoplastic lesions, which limits their proliferation and ultimately slows progression into pancreatic cancers.

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Section: Discussionsupporting

confidence: 87%

Oncogene-Induced Senescence Limits the Progression of Pancreatic Neoplasia through Production of Activin A

Zhao

Chanal

et al. 2020

Cancer Research

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“…Through transcriptional induction of p21/waf1, p53 can also suppress CDK, which in turn leads to the formation of repressive Rb/E2F complexes. The FOXM1 gene is a downstream target of E2F [ 47 ] and E2F expression was reduced by AKBA. In addition to inhibiting CDK1 via p21/waf1, p53 can also suppress the kinase activity by upregulating CDK1’s downstream target, GADD45A [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase

Wan

Liu

et al. 2018

J Exp Clin Cancer Res

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BackgroundGlioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.MethodsThe effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.ResultsAKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.ConclusionsTaken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0805-4) contains supplementary material, which is available to authorized users.

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“…Activin A is a well‐known repressor of liver regeneration, which terminates liver regeneration through phosphorylating mothers against decapentaplegic homolog 2 (smad2). [ 19 ] Intriguingly, its expression was found to be significantly decreased in GSDMD −/− mice at 48 hours and 72 hours after operation (Figure 6A ). A previous study showed that IL‐1β promotes the expression of activin A in skin fibroblasts, [ 20 ] and serum IL‐1β was significantly reduced in GSDMD −/− mice concurrently (Figure 6B ).…”

Section: Resultsmentioning

confidence: 97%

Gasdermin D–mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy

Chen

et al. 2022

Hepatol Commun

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Pyroptosis is a kind of programmed cell death primarily mediated by gasdermin D (GSDMD) and shown to regulate multiple diseases. However, its contribution to liver regeneration, a fine‐tuned tissue repair process mediated primarily by hepatocytes after mass loss, remains unclear. Herein, we found that caspase‐11/GSDMD‐mediated pyroptosis was activated in regenerating liver after 70% partial hepatectomy. Impeding pyroptosis by deleting GSDMD significantly reduced liver injury and accelerated liver regeneration. Mechanistically, GSDMD deficiency up‐regulates the activation of hepatocyte growth factor/c‐Met and epidermal growth factor receptor mitogenic pathways at the initiation phase. Moreover, activin A and glypican 3 (GPC3), two terminators of liver regeneration, were inhibited when GSDMD was absent. In vitro study suggested the expressions of activin A and GPC3 were induced by interleukin (IL)–1β and IL‐18, whose maturations were regulated by GSDMD‐mediated pyroptosis. Similarly, pharmacologically inhibiting GSDMD recapitulates these phenomena. Conclusion: This study characterizes the role of GSDMD‐mediated pyroptosis in liver regeneration and lays the foundation for enhancing liver restoration by targeting GSDMD in liver patients with impaired regenerative capacity.

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Activin A is a prominent autocrine regulator of hepatocyte growth arrest

Cited by 19 publications

References 49 publications

Oncogene-Induced Senescence Limits the Progression of Pancreatic Neoplasia through Production of Activin A

Oncogene-Induced Senescence Limits the Progression of Pancreatic Neoplasia through Production of Activin A

3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase

Gasdermin D–mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy

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