Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice

Xu Huang, Stephan Wullschleger, Natalia Shpiro, Victoria A. McGuire, Kei Sakamoto, Yvonne L. Woods, Wendy McBurnie, Stewart Fleming, Dario R. Alessi

    Research output: Contribution to journalArticle

    279 Citations (Scopus)

    Abstract

    The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1-AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN+/- mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN turnout suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.

    Original languageEnglish
    Pages (from-to)211-221
    Number of pages11
    JournalBiochemical Journal
    Volume412
    DOIs
    Publication statusPublished - 1 Jun 2008

    Keywords

    • AMP-activated protein kinase (AMPK)
    • cancer
    • LKB1
    • mammalian target of rapamycin (mTOR)
    • metformin
    • phosphatase and tensin homologue deleted on chromosome 10 (PTEN)
    • ACTIVATED PROTEIN-KINASE
    • PEUTZ-JEGHERS-SYNDROME
    • TUMOR-SUPPRESSOR
    • CANCER-CELLS
    • ENERGETIC STRESS
    • CELLULAR-ENERGY
    • SKELETAL-MUSCLE
    • LKB1
    • MUTATION
    • METFORMIN

    Cite this

    Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., ... Alessi, D. R. (2008). Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochemical Journal, 412, 211-221. https://doi.org/10.1042/BJ20080557
    Huang, Xu ; Wullschleger, Stephan ; Shpiro, Natalia ; McGuire, Victoria A. ; Sakamoto, Kei ; Woods, Yvonne L. ; McBurnie, Wendy ; Fleming, Stewart ; Alessi, Dario R. / Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. In: Biochemical Journal. 2008 ; Vol. 412. pp. 211-221.
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    abstract = "The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1-AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN+/- mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN turnout suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.",
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    Huang, X, Wullschleger, S, Shpiro, N, McGuire, VA, Sakamoto, K, Woods, YL, McBurnie, W, Fleming, S & Alessi, DR 2008, 'Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice', Biochemical Journal, vol. 412, pp. 211-221. https://doi.org/10.1042/BJ20080557

    Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. / Huang, Xu; Wullschleger, Stephan; Shpiro, Natalia; McGuire, Victoria A.; Sakamoto, Kei; Woods, Yvonne L.; McBurnie, Wendy; Fleming, Stewart; Alessi, Dario R.

    In: Biochemical Journal, Vol. 412, 01.06.2008, p. 211-221.

    Research output: Contribution to journalArticle

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    T1 - Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice

    AU - Huang, Xu

    AU - Wullschleger, Stephan

    AU - Shpiro, Natalia

    AU - McGuire, Victoria A.

    AU - Sakamoto, Kei

    AU - Woods, Yvonne L.

    AU - McBurnie, Wendy

    AU - Fleming, Stewart

    AU - Alessi, Dario R.

    PY - 2008/6/1

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    N2 - The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1-AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN+/- mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN turnout suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.

    AB - The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1-AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN+/- mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN turnout suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.

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    KW - phosphatase and tensin homologue deleted on chromosome 10 (PTEN)

    KW - ACTIVATED PROTEIN-KINASE

    KW - PEUTZ-JEGHERS-SYNDROME

    KW - TUMOR-SUPPRESSOR

    KW - CANCER-CELLS

    KW - ENERGETIC STRESS

    KW - CELLULAR-ENERGY

    KW - SKELETAL-MUSCLE

    KW - LKB1

    KW - MUTATION

    KW - METFORMIN

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    JO - Biochemical Journal

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    SN - 0264-6021

    ER -

    Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochemical Journal. 2008 Jun 1;412:211-221. https://doi.org/10.1042/BJ20080557