AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells

Santidrián, Antonio F.; González-Gironès, Diana M.; Iglesias-Serret, Daniel; Coll-Mulet, Llorenç; Cosialls, Ana M.; Frías, Mercè de; Campàs, Clara; González‐Barca, Eva; Alonso, Esther; Labi, Verena; Viollet, Benoı̂t; Benito, Adalberto; Pons, Gabriel; Villunger, Andreas; Gil, Joan

doi:10.1182/blood-2010-05-283960

Cited by 98 publications

(95 citation statements)

References 51 publications

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“…Recently, Meisse et al (2002) reported that AICAR induces apoptosis independently of AMPK status in chronic lymphocytic leukemia cells (Santidrian et al 2010). This finding encouraged us to identify the signaling molecules involved in mediating the anti-proliferative effects of AICAR in thyroid cancer cells harboring the BRAF V600E mutation.…”

Section: Analysis Of Aicar-induced Effects On Signal Transduction In mentioning

confidence: 99%

The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

Choi

Kim

Chung³

et al. 2011

Journal of Endocrinology

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5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 50 -AMP-activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPKmediated growth inhibition is achieved via an action of the RAF-MEK-ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anticancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects.AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600E-mutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR-induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation.

show abstract

Section: Analysis Of Aicar-induced Effects On Signal Transduction In mentioning

confidence: 99%

The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

Choi

Kim

Chung³

et al. 2011

Journal of Endocrinology

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“…24 As a consequence, a safety and tolerability open label phase I dose escalation study of AICAR in B-CLL patients is ongoing (ClinicalTrial.gov, identifier: NCT00559624).…”

Section: Lkb1/ampk In Hematological Malignanciesmentioning

confidence: 99%

LKB1/AMPK/mTOR signaling pathway in hematological malignancies: From metabolism to cancer cell biology

Green¹,

Chapuis²,

Lacombe³

et al. 2011

Cell Cycle

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“…Although AICAR does inhibit proliferation (11)(12)(13)(14)(15), it also causes AMPK-independent cellular and metabolic effects (12,16) including inhibition of glucokinase, glycogen phosphorylase, and nucleotide biosynthesis (17,18). Whether AICAR requires AMPK to suppress proliferation is questionable because although both AICAR and 2-deoxyglucose activated AMPK, only AICAR inhibited proliferation of trisomic mouse fibroblasts (11).…”

mentioning

confidence: 99%

Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK

Liu¹,

Chhipa²,

Pooya³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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198

190

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The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesistwo crucial arms of cancer growth-AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents.metabolism | glioma A MP-activated protein kinase (AMPK) is a molecular hub for cellular metabolic control (1-4). It is a heterotrimer of catalytic α, regulatory β, and γ subunits. The rising AMP:ATP ratio during energy stress leads to AMP-dependent phosphorylation of the catalytic α subunits. This activates AMPK which then phosphorylates numerous substrates to restore energy homeostasis. It phosphorylates acetyl CoA carboxylase (ACCα) to inhibit fatty acid (FA) synthesis (5) and TSC2 and RAPTOR (6, 7) to inhibit mammalian target of rapamycin (mTOR)C1. Because fatty acid synthesis and mTORC1 activity are essential for cell proliferation and growth (8), AMPK activation with two indirect AMPK agonists AICAR and metformin have been correlated with suppression of cell proliferation and growth (9-11).AICAR is metabolized to an AMP mimetic, ZMP that activates AMPK (12). Although AICAR does inhibit proliferation (11-15), it also causes AMPK-independent cellular and metabolic effects (12, 16) including inhibition of glucokinase, glycogen phosphorylase, and nucleotide biosynthesis (17, 18). Whether AICAR requires AMPK to suppress proliferation is questionable because although both AICAR and 2-deoxyglucose activated AMPK, only AICAR inhibited proliferation of trisomic mouse fibroblasts (11). Moreover, although AICAR strongly increases glucose uptake through AMPK activation in muscle cells, it reduced fluorodeoxyglucose-PET signals and inhibited glioma gro...

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AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells

Cited by 98 publications

References 51 publications

The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

LKB1/AMPK/mTOR signaling pathway in hematological malignancies: From metabolism to cancer cell biology

Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK

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