Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells

Wang, Sen; Wang, Kexin; Zhang, Chundong; Zhang, Wanfeng; Xu, Qian; Wang, Yitao; Zhang, Yulin; Li, Yang; Zhang, Ying; Zhu, Hui; Song, Fangzhou; Y, Lei; Bu, Youquan

doi:10.1038/cddis.2017.485

Cited by 45 publications

(33 citation statements)

References 77 publications

(105 reference statements)

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“…Increasing evidence implicates a dual role of autophagy in cancer therapy, i.e., protecting cell survival and promoting cell apoptosis (51,63). It has been reported that the blocking of autophagy increases erianin or betulinic acid-induced apoptosis (64,65). In the present study, it was found that the inhibition of autophagy by cQ or siATG5 enhanced the UA-induced inhibition of cell proliferation and promoted the UA-induced apoptosis (Figs.…”

Section: Discussionsupporting

confidence: 61%

Autophagy inhibition enhances the inhibitory�effects of ursolic acid on lung cancer cells

Wang

et al. 2020

Int J Mol Med

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The aim of the present study was to identify natural compounds that bear significant anti-tumor activity. Thus, the effects of 63 small molecules that were isolated from traditional chinese medicinal herbs on A549 human non-small cell lung cancer (NScLc) and McF-7 breast cancer cells were examined. It was found that ursolic acid (UA), a natural pentacyclic triterpenoid, exerted significant inhibitory effect on these cells. Further experiments revealed that UA inhibited the proliferation of various lung cancer cells, including the NScLc cells, H460, H1975, A549, H1299 and H520, the human small cell lung cancer (ScLc) cells, H82 and H446, and murine Lewis lung carcinoma (LLc) cells. UA induced the apoptosis and autophagy of NSCLC cells. The inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, but not the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway contributed to the UA-induced autophagy of NSCLC cells. Moreover, the inhibition of autophagy by chloroquine (cQ) or siRNA for autophagy-related gene 5 (ATG5) enhanced the UA-induced inhibition of cell proliferation and promotion of apoptosis, indicating that UA-induced autophagy is a pro-survival mechanism in NSCLC cells. On the whole, these findings suggest that combination treatment with autophagy inhibitors may be a novel strategy with which enhance the antitumor activity of UA in lung cancer.

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Section: Discussionsupporting

confidence: 61%

Autophagy inhibition enhances the inhibitory�effects of ursolic acid on lung cancer cells

Wang

et al. 2020

Int J Mol Med

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“…[24][25][26] Furthermore, BA has shown tumorigenesis inhibition in many kinds of cancers, including lung, colon, breast, prostate and pancreatic cancer. [27][28][29][30] In the present study, our results showed that BA distinctly triggered apoptosis and suppressed the proliferation, migration and invasion of GC cells in vitro. The in vivo anti-tumour efficacy was consistent with that reported in vitro studies.…”

Section: Introductionsupporting

confidence: 62%

“…32 It is widely reported that BA is cytotoxic to various types of human cancer cells. [28][29][30] In the present study, we assessed the antitumour effect of BA on human GC cells in vitro and in vivo. nalling pathway and inhibits hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Betulinic acid triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress

Chen

Liu

et al. 2020

Cell Biochemistry & Function

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Gastric cancer (GC) is one of the most prevalent types of malignancies. Betulinic acid (BA) is a natural pentacyclic triterpene with a lupine structure. However, to the best of our knowledge, there is no research study on the anti-tumour and anti-metastasis effect of BA on GC. In this study, we assessed the anti-cancer effect of BA on human GC cells in vitro and in vivo. We first investigated the cytotoxicity and antiproliferation effect of BA on GC cells of SNU-16 and NCI-N87. The results indicated that BA had significant cytotoxic and inhibitory effects on GC cells in a dose-and time-dependent manner. To further study the cytotoxic action of BA on GC cells, we assessed the apoptotic induction effect of BA on SNU-16 cells and found that BA distinctly induced apoptosis in SNU-16 cells. In addition, BA inhibited the migratory and invasive abilities of SNU-16 cells. Western-blot analysis revealed that BA suppressed the migration and invasion of GC cells by impairing epithelialmesenchymal transition progression. Furthermore, in vivo experiments showed that BA could delay tumour growth and inhibit pulmonary metastasis, which is consistent with the results of in vitro studies. Overall, we evaluated the anti-cancer effect of BA on human GC cells in vivo and in vitro, and the present study provides new evidence on the use of BA as a potential anti-cancer drug for GC treatment. Significance of the study: BA significantly suppressed proliferation and triggered apoptosis in GC cells. Additionally, BA remarkably inhibited migration and invasion of GC cells by impairing the epithelial-mesenchymal transition signalling pathway. It is worth noting that BA drastically retarded tumour growth in the xenograft mouse model of GC. Our results indicated that BA can be considered a candidate drug for GC therapy.

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“…Other studies have also confirmed that autophagy is involved in BA-mediated cancer death. 49,50 BA induced cell death via reducing the overaccumulation of its protective autophagy through ubiquitin-mediated degradation pathway in colorectal cancer cells, 49 while it promoted cell death through the inhibition of autophagic flux in multiple myeloma cells. 50 We also further studied the involvement of the autophagy pathway.…”

Section: Discussionmentioning

confidence: 99%

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

Chen

Zhong

Tan

et al. 2020

Clinical & Translational Med

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Betulinic acid (BA) is a natural product extracted from a broad range of medicinal and edible herbal plants. Previous studies showed that BA induces cell death in tumors derived from multiple tissues; however, the underlying mechanism remains obscure. The present study aimed to study the effects of BA on autophagy and apoptosis of hepatocellular carcinoma (HCC). Human HCC cell lines and orthotopic HCC implanted mice were employed to examine the BA‐induced tumor suppression; RT 2 long noncoding RNA (lncRNA) PCR array and database analysis were used to explore the possible mechanisms; validation of pathways was performed using siRNA and miRNA inhibitors. The results indicated that BA regulated autophagy and induced apoptosis in HCC. The degradation of inhibitor of apoptosis proteins (IAPs), the conversion of LC3‐I to LC3‐II, and p62 accumulation were enhanced by BA, thereby suggesting that the downregulation of IAPs and autophagic cell death are induced by BA. The addition of autophagy and lysosomal inhibitors indicated that BA induced autophagy‐independent apoptosis via degradation of IAPs. Moreover, RT 2 lncRNA PCR array and database analysis suggested that BA downregulated the levels of lncRNA MALAT1, which is considered to be an oncogene. Further investigations demonstrated that lncRNA MALAT1 functioned as a ceRNA (competing endogenous RNA) to contribute to BA‐mediated degradation of IAPs by sponging miR‐22‐3p. Therefore, BA could be developed as a potential anticancer agent for HCC.

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Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells

Cited by 45 publications

References 77 publications

Autophagy inhibition enhances the inhibitory�effects of ursolic acid on lung cancer cells

Autophagy inhibition enhances the inhibitory�effects of ursolic acid on lung cancer cells

Betulinic acid triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

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