Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling

Sun, Liankang; Cao, Junyu; Chen, Ke; Liu, Cheng; Zhou, Cancan; Yan, Bin; Qian, Weikun; Li, Jie; Duan, Wanxing; Ma, Jiguang; Qi, Dan; Wu, Erxi; Wang, Zheng; Liu, Qingguang; Ma, Qingyong; Xu, Qinhong

doi:10.3892/ijo.2018.4604

Cited by 31 publications

(35 citation statements)

References 53 publications

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“…PVDF membranes were blocked with 5% dry milk for 1 h. Membranes were incubated in the primary antibody overnight at 4°C. The following antibodies were used in Western blotting: PRR [18] (1:1,000; anti-ATP6IP2/ab40790, Abcam, MA), PGC-1α [19] (1:1000, ab54481, Abcam), NRF-1 [20] (1:1000, ab34682, Abcam, MA), mtTFA [21] (1:1000, ab131607, Abcam), p-AMPK [22, 23] (1:1000, 2535S, CST), t-AMPK [23] (1:1000, 2532S, CST), SIRT-1 [24] (1:1000, 9475S, CST). The membranes were then incubated with the corresponding secondary antibody (1:2000, horseradish peroxidase-conjugated anti-rabbit) in TBST-5% nonfat milk for 1 h at room temperature, and the immunoreactive bands were visualized followed by incubation with horseradish peroxidase-labeled IgG (1:5000).…”

Section: Methodsmentioning

confidence: 99%

Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney

Akhtar

Siragy

2019

PLoS ONE

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Abnormal mitochondrial biogenesis and function has been linked to multiple diseases including diabetes. Recently, we demonstrated the role of renal (Pro)renin receptor (PRR) in the dysregulation of mitochondria. We hypothesized that PRR contributes to the reduction of mitochondrial biogenesis and function in diabetic kidney via PGC-1α/AMPK/SIRT-1 signaling pathway. In vivo and in vitro studies were conducted in C57BL/6 mouse and mouse renal mesangial cells (mRMCs). Control and streptozotocin-induced diabetic mice were injected with scramble or PRR shRNA and followed for a period of eight weeks. PRR mRNA and protein expression increased by 44% and 39% respectively (P<0.05) in kidneys of diabetic mice, and in mRMCs exposed to high glucose by 43 and 61% respectively compared to their respective controls. These results were accompanied by reduced mRNA and protein expressions of PGC-1α (67% and 75%), nuclear respiratory factors (NRF-1, 48% and 53%), mitochondrial transcriptional factor A (mtTFA, 56% and 40%), mitochondrial DNA copy number by 75% (all, P<0.05), and ATP production by 54%, respectively in diabetic kidneys and in mRMCs exposed to high glucose. Compared to non-diabetic control mice, PRR knockdown in diabetic mice and in mRMCs, not only attenuated the PRR mRNA and protein expression but also normalized mRNA and protein expressions of PGC-1α, NRF-1, mtTFA, mitochondrial DNA copy number, and ATP production. Treatment with AMPK inhibitor, Compound C, or SIRT-1 inhibitor, EX-527, alone, or combined with PRR siRNA caused marked reduction of mRNA expression of PGC-1α, NRF-1 and mtTFA, and ATP production in mRMCs exposed to high glucose. In conclusion, our study demonstrated the contribution of the PRR to the reduction of mitochondrial biogenesis and function in diabetic kidney disease via decreasing AMPK/SIRT-1/ PGC-1α signaling pathway.

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Section: Methodsmentioning

confidence: 99%

Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney

Akhtar

Siragy

2019

PLoS ONE

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“…The silencing of AMPK could abrogate the reverse of the mesenchymal phenotype among breast and prostate cancer cell lines. Other researches demonstrated that AMPK could suppress EMT of pancreatic cancer and hepatocellular carcinoma cells (90)(91)(92). In the previous researches, specific AMPK activators or inhibitors were used to evaluate AMPK-mediated EMT.…”

Section: Ampkmentioning

confidence: 99%

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

2020

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Metastasis is the main cause of cancer-related mortality. Although the actual process of metastasis remains largely elusive, epithelial-mesenchymal transition (EMT) has been considered as a major event in metastasis. Besides, hypoxia is common in solid cancers and has been considered as an important factor for adverse treatment outcomes including metastasis. Since EMT and hypoxia potentially share several signaling pathways, many recent studies focused on investigate the issue of hypoxia-induced EMT. Among all potential mediators of hypoxia-induced EMT, hypoxia-inducible factor-1α (HIF-1α) has been studied extensively. Moreover, there are other potential mediators that may also contribute to the process. This review aims to summarize the recent reports on hypoxia-induced EMT by HIF-1α or other potential mediators and provide insights for further investigations on this issue. Ultimately, better understanding of hypoxia-induced EMT may allow us to develop anti-metastatic strategies and improve treatment outcomes.

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“…Previous study demonstrated that BA triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress (Chen et al., 2020). Sun et al showed that BA can inhibit stemness and EMT of pancreatic cancer cells via activation of AMPK signaling (Sun et al., 2019). Furthermore, BA suppressed NGAL‐induced epithelial‐to‐mesenchymal transition in melanoma (Gheorgheosu et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

Betulinic acid induces apoptosis and impairs migration and invasion in a mouse model of ovarian cancer

et al. 2020

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Betulinic acid (BA) was verified to possess plenty of biological activities including anti‐tumor, anti‐inflammatory and so on. In our research, we studied the growth inhibition, apoptosis promotion and metastasis resistance of ovarian cancer cells by BA. The result showed that BA showed a time‐ and dose‐dependent inhibitory effect on ovarian cancer cell lines. SKOV3 cell line proliferation has a concentration‐ and time‐dependently, which may be inhibited by BA. Furthermore, BA inhibited the metastasis of tumor cells remarkably by inhibiting epithelial‐mesenchymal transition process. Beyond that, the weight and volume of subcutaneous tumor was distinctly suppressed by administration of BA in tumor‐bearing mice of SKOV3 cells. Pathological and immunohistochemical tests showed that Ki‐67+ and MMP‐2+ cells were dramatically decreased after BA administration, indicating that BA can not only suppress proliferation, but also inhibit migration of tumor cells. Taken together, BA can be a valuable candidate drug for the treatment of ovarian cancer. Practical applications Betulinic acid (BA) isolated from natural plants such as fenugreek, eucalyptus bulb and mulberry has been reported with many biological activities. Results from this study revealed that in vitro and in vivo BA‐induced apoptosis and inhibited migration and invasion of human ovarian cancer cells. Therefore, BA from natural plants may be developed as a potential drug for inhibition the development of ovarian cancer cells.

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Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling

Cited by 31 publications

References 53 publications

Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney

Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney

Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond

Betulinic acid induces apoptosis and impairs migration and invasion in a mouse model of ovarian cancer

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