Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3

S. Sengupta, Arumugam Nagalingam, N. Muniraj, M. Y. Bonner, P. Mistriotis, A. Afthinos, P. Kuppusamy, D. Lanoue, S. Cho, Preethi Korangath, M. Shriver, Asma Begum, Vanessa Merino, C. Y. Huang, J. L. Arbiser, W. Matsui, B. Györffy, K Konstantopoulos, Saraswati Sukumar, P. A. Marignani & 2 others N. K. Saxena, Dipali Sharma

Research output: Contribution to journalArticle

Abstract

Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1- / - mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1- silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivationfunction of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

Original languageEnglish (US)
Pages (from-to)5709-5721
Number of pages13
JournalOncogene
Volume36
Issue number41
DOIs
StatePublished - Oct 12 2017

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Phosphotransferases
Breast Neoplasms
Phenotype
Liver
Neoplasms
Adenosine Monophosphate
Protein Kinases
honokiol
Magnolia
Null Lymphocytes
Aldehyde Dehydrogenase
Neoplastic Stem Cells
Heterografts
Cell Movement
Carcinogenesis
Breast
Binding Sites
Phosphorylation
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. / Sengupta, S.; Nagalingam, Arumugam; Muniraj, N.; Bonner, M. Y.; Mistriotis, P.; Afthinos, A.; Kuppusamy, P.; Lanoue, D.; Cho, S.; Korangath, Preethi; Shriver, M.; Begum, Asma; Merino, Vanessa; Huang, C. Y.; Arbiser, J. L.; Matsui, W.; Györffy, B.; Konstantopoulos, K; Sukumar, Saraswati; Marignani, P. A.; Saxena, N. K.; Sharma, Dipali.

In: Oncogene, Vol. 36, No. 41, 12.10.2017, p. 5709-5721.

Research output: Contribution to journalArticle

Sengupta, S, Nagalingam, A, Muniraj, N, Bonner, MY, Mistriotis, P, Afthinos, A, Kuppusamy, P, Lanoue, D, Cho, S, Korangath, P, Shriver, M, Begum, A, Merino, V, Huang, CY, Arbiser, JL, Matsui, W, Györffy, B, Konstantopoulos, K, Sukumar, S, Marignani, PA, Saxena, NK & Sharma, D 2017, 'Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3', Oncogene, vol. 36, no. 41, pp. 5709-5721. https://doi.org/10.1038/onc.2017.164
Sengupta, S. ; Nagalingam, Arumugam ; Muniraj, N. ; Bonner, M. Y. ; Mistriotis, P. ; Afthinos, A. ; Kuppusamy, P. ; Lanoue, D. ; Cho, S. ; Korangath, Preethi ; Shriver, M. ; Begum, Asma ; Merino, Vanessa ; Huang, C. Y. ; Arbiser, J. L. ; Matsui, W. ; Györffy, B. ; Konstantopoulos, K ; Sukumar, Saraswati ; Marignani, P. A. ; Saxena, N. K. ; Sharma, Dipali. / Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. In: Oncogene. 2017 ; Vol. 36, No. 41. pp. 5709-5721.
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abstract = "Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1- / - mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1- silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivationfunction of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.",
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AU - Sengupta, S.

AU - Nagalingam, Arumugam

AU - Muniraj, N.

AU - Bonner, M. Y.

AU - Mistriotis, P.

AU - Afthinos, A.

AU - Kuppusamy, P.

AU - Lanoue, D.

AU - Cho, S.

AU - Korangath, Preethi

AU - Shriver, M.

AU - Begum, Asma

AU - Merino, Vanessa

AU - Huang, C. Y.

AU - Arbiser, J. L.

AU - Matsui, W.

AU - Györffy, B.

AU - Konstantopoulos, K

AU - Sukumar, Saraswati

AU - Marignani, P. A.

AU - Saxena, N. K.

AU - Sharma, Dipali

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