miR-1273g silences MAGEA3/6 to inhibit human colorectal cancer cell growth via activation of AMPK signaling

Wu, Fang; Liu, Fang; Dong, Lemei; Han, Yang; He, Xixi; Li, Lili; Li, Zhao; Jin, Sisi; Li, Gang

doi:10.1016/j.canlet.2018.07.031

Cited by 41 publications

(37 citation statements)

References 43 publications

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“…Therefore, mTOR signaling has been described as an important target for cancer diagnosis. Multiple reports have demonstrated that the activation of AMPK signaling is capable of suppressing mTORC1 activation [9,50,51]. This AMPK inhibitory effect on mTOR in tumor cells occurs by two distinct pathways: (1) AMPK phosphorylates TSC2 at Ser 1345 , which stimulates its Rheb-GAP activity; (2) AMPK phosphorylates Raptor at Ser 722 and Ser 792 which are both reasonably well conserved throughout eukaryotes [52][53][54].…”

Section: Discussionmentioning

confidence: 99%

“…AMP-activated protein kinase (AMPK), a conserved serine/threonine kinase, is nearly ubiquitous in eukaryotes and is regulator of cellular energy and nutrient uptake in response to cellular stress, including hypoxia, exercise, and starvation [9]. AMPK is a heterotrimeric complex, and is composed of a catalytic α subunit and regulatory β and γ subunits.…”

Section: Introductionmentioning

confidence: 99%

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Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway

et al. 2020

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Colorectal cancer (CRC) is a leading cause of cancer-related human deaths. The exopolysaccharide (EPS1-1), isolated from Rhizopus nigricans, has been described as exhibiting anti-tumor and pro-apoptotic activity against CRC, although the underlying mechanism is poorly understood. Herein, we investigate how EPS1-1 induces apoptosis of CRC cells in vitro and in vivo. Our results show that, in vitro, EPS1-1 suppressed cell growth and facilitated apoptosis in a dose- and time-dependent manner by activating the AMP-activated protein kinase (AMPK) pathway in mouse colon cancer CT26 cells. However, treatment with small interfering RNAs (siRNAs) targeting AMPKα or with compound C, an AMPK inhibitor, interfered with the pro-apoptosis effects of EPS1-1. We also show that EPS1-1 initiated the release of reactive oxygen species (ROS) and liver kinase B1 (LKB1), both of which are necessary signals for AMPK activation. Furthermore, EPS1-1-mediated apoptosis is regulated by inactivation of mammalian target of rapamycin complex 1 (mTORC1) and activation of the jun-NH2 kinase (JNK)-p53 signaling axis dependent on AMPK activation. In vivo, azoxymethane/dextran sulfate sodium (AOM/DSS)-treated CRC mice, when administered EPS1-1, exhibited activation of the AMPK pathway, inhibition of mTORC1, and accumulation of p53 in tumor tissues. Collectively, these findings suggest that EPS1-1-induced apoptosis relies on the activation of the AMPK pathway. The present study provides evidence suggesting that EPS1-1 may be an effective target for development of novel CRC therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway

et al. 2020

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“…6a). Although there is evidence suggesting that AMPK might help cancer cells survive under certain circumstances 25 , there is more support in the literature for the notion that AMPK acts as a tumor suppressor by leading to cell growth inhibition and cell cycle arrest [26][27][28][29] . In particular, AMPK activation has proven to be an effective strategy to inhibit pancreatic cancer cell growth [30][31][32] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

et al. 2019

Cell Death Dis

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Pancreatic cancer is a highly malignant cancer and lacks effective therapeutic targets. Protein-tyrosine phosphatase 1B (PTP1B), a validated therapeutic target for diabetes and obesity, also plays a critical positive or negative role in tumorigenesis. However, the role of PTP1B in pancreatic cancer remains elusive. Here, we initially demonstrated that PTP1B was highly expressed in pancreatic tumors, and was positively correlated with distant metastasis and tumor staging, and indicated poor survival. Then, inhibition of PTP1B either by shRNA or by a specific small-molecule inhibitor significantly suppressed pancreatic cancer cell growth, migration and colony formation with cell cycle arrest in vitro and inhibited pancreatic cancer progression in vivo. Mechanism studies revealed that PTP1B targeted the PKM2/ AMPK/mTOC1 signaling pathway to regulate cell growth. PTP1B inhibition directly increased PKM2 Tyr-105 phosphorylation to further result in significant activation of AMPK, which decreased mTOC1 activity and led to inhibition of p70S6K. Meanwhile, the decreased phosphorylation of PRAS40 caused by decreased PKM2 activity also helped to inhibit mTOC1. Collectively, these findings support the notion of PTP1B as an oncogene and a promising therapeutic target for PDAC.

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“…Importantly, MAGE-A3/6 drives cellular transformation, tumor growth, and metastasis [10,16,18]. Specifically, MAGE-A3/6 drives ubiquitination and degradation of two key metabolic enzymes and tumor suppressors, 5 0 adenosine monophosphate-activated protein kinase (AMPK) and fructose-1,6-bisphosphatase 1 (FBP1), by the TRIM28 E3 ubiquitin ligase [10,[19][20][21][22]. Specifically, MAGE-A3/6 drives ubiquitination and degradation of two key metabolic enzymes and tumor suppressors, 5 0 adenosine monophosphate-activated protein kinase (AMPK) and fructose-1,6-bisphosphatase 1 (FBP1), by the TRIM28 E3 ubiquitin ligase [10,[19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Regulation of MAGE ‐A3/6 by the CRL 4‐ DCAF 12 ubiquitin ligase and nutrient availability

et al. 2019

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Melanoma antigen genes (MAGEs) are emerging as important oncogenic drivers that are normally restricted to expression in male germ cells but are aberrantly expressed in cancers and promote tumorigenesis. Mechanistically, MAGEs function as substrate specifying subunits of E3 ubiquitin ligases. Thus, the activation of germline-specific genes in cancer can drive metabolic and signaling pathways through altered ubiquitination to promote tumorigenesis. However, the mechanisms regulating MAGE expression and activity are unclear. Here, we describe how the MAGE-A3/6 proteins that function as repressors of autophagy are downregulated in response to nutrient deprivation. Short-term cellular starvation promotes rapid MAGE-A3/6 degradation in a proteasome-dependent manner. Proteomic analysis reveals that degradation of MAGE-A3/6 is controlled by the CRL4-DCAF12 E3 ubiquitin ligase. Importantly, the degradation of MAGE-A3/6 by CRL4-DCAF12 is required for starvation-induced autophagy. These findings suggest that oncogenic MAGEs can be dynamically controlled in response to stress to allow cellular adaptation, autophagy regulation, and tumor growth and that CRL4-DCAF12 activity is responsive to nutrient status.

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miR-1273g silences MAGEA3/6 to inhibit human colorectal cancer cell growth via activation of AMPK signaling

Cited by 41 publications

References 43 publications

Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway

Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

Regulation of MAGE ‐A3/6 by the CRL 4‐ DCAF 12 ubiquitin ligase and nutrient availability

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