Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Sauer, Heinrich; Engel, S.; Milosevic, Nada; Sharifpanah, Fatemeh; Wartenberg, Maria

doi:10.3892/ijo.2011.1230

Cited by 34 publications

(30 citation statements)

References 37 publications

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“…Among the signaling pathways regulated by AMPK, mTOR is known to perform a central role in antitumor activity (23). Recently, several compounds, including metformin and myrtucommulone A, have been reported to exert antileukemia activity via activation of the AMPK/mTOR signaling pathway (24,25). Similarly, the present results revealed that adenine suppressed the viability of K562 cells through activation of the AMPK/mTOR signaling pathway, resulting in G 2 /M phase arrest and autophagic cell death.…”

Section: Discussionsupporting

confidence: 66%

Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Chen

Lin

et al. 2017

Oncol Lett

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Abstract. AMP-activated protein kinase (AMPK) is known as a pivotal regulator of cellular metabolism. Mounting evidences have demonstrated that AMPK activation exerts tumor suppressive activity on leukemia cells. The present study reported that adenine, an AMPK activator, triggers cell cycle arrest and autophagy of human chronic myelogenous leukemia K562 cells consequently suppressing cell viability. The present findings revealed that adenine treatment (4.0-8.0 mM) significantly inhibited the viability of K562 cells to 69.3±2.5% (24 h) and 53.4±2.1% (48 h) of the control. Flow cytometric analysis revealed that there was a significant accumulation in G 2 /M phase, but not sub-G 1 phase K562 cells following exposure to adenine. Additional investigation demonstrated that adenine treatments significantly increased the number of acidic vesicular organelles and the level of autophagosomal microtubule associated protein 1 light chain 3 α (LC3) marker. By contrast, cleavage of caspase-9, caspase-3 and poly-ADPribose polymerase was insignificantly affected in K562 cells following adenine treatment. In K562 cells, adenine was able to markedly promote the phosphorylation of AMPKα and suppress the phosphorylation of mammalian target of rapamycin (mTOR), a downstream target of AMPK. In addition, inhibiting AMPK phosphorylation using dorsomorphin restored mTOR phosphorylation, inhibited the accumulation of LC3 and significantly recovered the suppressed cell viability in response to adenine. Taken together, the present results demonstrated that adenine induced G 2 /M phase arrest and autophagic cell death, consequently suppressing the viability of K562 cells, which may attribute to the AMPK activation triggered by adenine. These findings provide evidence that adenine may be beneficial to chronic myelogenous leukemia therapy by suppressing excessive cell proliferation.

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Section: Discussionsupporting

confidence: 66%

Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Chen

Lin

et al. 2017

Oncol Lett

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“…The apoptosis induced by Orlistat and AICAR co-treatment is preceded by an increase in ROS production and caspase 9 and 3 activation (Figure 4). AICAR has been reported to inhibit cell growth and induce apoptosis in DU145 PCa cells in a ROS and caspase 3-dependent manner [Sauer et al, 2012]. AICAR has also been implicated in the potentiation of ROS production induced by high glucose levels in pancreatic beta cells [Kim et al, 2007].…”

Section: Discussionmentioning

confidence: 99%

Anti‐Tumorigenic Potential of a Novel Orlistat‐AICAR Combination in Prostate Cancer Cells

Wright

Iyer

Kaushik

et al. 2017

J of Cellular Biochemistry

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Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men worldwide. Fatty acid synthase (FASN) is reported to be overexpressed in several cancers including PCa, and this has led to clinical cancer treatments that utilize various FASN inhibitors such as the anti-obesity drug, Orlistat. However, pharmacological limitations have impeded the progress in cancer treatments expected thus far with FASN inhibition. In this study, we investigated a novel therapeutic combination to enhance the toxic potential of Orlistat in three different PCa cell-lines (DU145, PC3, and LNCaP). We show that Orlistat and 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (AMP-activated protein kinase (AMPK) activator) co-treatment induces significant downregulation of two key fatty acid synthesis regulatory proteins (FASN, Sterol regulatory element-binding protein 1 (SREBP-1c)) as compared to control and Orlistat alone. Orlistat and AICAR co-treatment induced a significant decrease in cell viability and proliferation, and a significant increase in apoptosis in all three PCa cell-lines. Apoptosis induction was preceded by a marked increase in reactive oxygen species (ROS) production followed by G0/G1 cell cycle arrest and activation of pro-apoptotic caspases. We also observed a significant decrease in migration potential and VEGF expression in Orlistat and AICAR co-treated samples in all three PCa cell-lines. Compound C (AMPK inhibitor) negatively affected the enhanced effects of Orlistat and AICAR co-treatment. We conclude that AICAR co-treatment potentiates the anti-proliferative effects of Orlistat at a low dose (100 μM), and this combination has the potential to be a viable and effective therapeutic option in PCa treatment.

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“…In line with this, pharmacologic activation of AMPK has been reported to decrease growth and viability of several prostate cancer cell lines in vitro and to inhibit lipid synthesis induced by the synthetic androgen R1881 [26]. Multiple mechanisms may contribute to these effects of AMPK, including inhibition of the mTOR pathway, up-regulation of p53 and p21 [27] and induction of apoptosis through generation of reactive oxygen species as well as through cross-talk with TNF signalling [28, 29]. In addition to its anti-proliferative effects, AMPK may also enhance the sensitivity of cancer cells to therapeutic treatments.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis reveals inhibition of androgen receptor activity by AMPK in prostate cancer cells

et al. 2014

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Metabolic alterations contribute to prostate cancer development and progression; however, the role of the central metabolic regulator AMP-activated protein kinase (AMPK) remains controversial. The androgen receptor (AR), a key driver of prostate cancer, regulates prostate cancer cell metabolism by driving the expression of a network of metabolic genes and activates AMPK through increasing the expression of one of its upstream kinases. To more clearly define the role of AMPK in prostate cancer, we performed expression profiling following pharmacologic activation of this kinase. We found that genes down-regulated upon AMPK activation were over-expressed in prostate cancer, consistent with a tumour suppressive function of AMPK. Strikingly, we identified the AR as one of the most significantly enriched transcription factors mediating gene expression changes downstream of AMPK signalling in prostate cancer cells. Activation of AMPK inhibited AR transcriptional activity and reduced androgen-dependent expression of known AR target genes. Conversely, knock-down of AMPK increased AR activity. Modulation of AR expression could not explain these effects. Instead, we observed that activation of AMPK reduced nuclear localisation of the AR. We thus propose the presence of a negative feedback loop in prostate cancer cells whereby AR activates AMPK and AMPK feeds back to limit AR-driven transcription.

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Activation of AMP-kinase by AICAR induces apoptosis of DU-145 prostate cancer cells through generation of reactive oxygen species and activation of c-Jun N-terminal kinase

Cited by 34 publications

References 37 publications

Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling

Anti‐Tumorigenic Potential of a Novel Orlistat‐AICAR Combination in Prostate Cancer Cells

Transcriptomic analysis reveals inhibition of androgen receptor activity by AMPK in prostate cancer cells

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