Molecular Targets of Honokiol

Averett, Courey; Arora, Sumit; Zubair, Haseeb; Singh, Seema; Bhardwaj, Arun; Singh, Ajay P.

doi:10.1016/b978-0-12-802215-3.00009-4

Cited by 16 publications

(11 citation statements)

References 76 publications

(111 reference statements)

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“…23,24 The bioactive compound responsible for the medicinal effects of Magnolia species is a phenolic compound, HNK. Using various in vitro and in vivo models, our research group has shown that HNK inhibits breast carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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 coactivation-function 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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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Honokiol and resveratrol are natural products that increase Sirt3 expression and modulate Sirt3 activity, and have high bioavailability ( 14 , 35 ). These agents possess anti-inflammatory, anti-apoptotic and anti-oxidant properties, as well as AMP activated protein kinase activation and induction of autophagy abilities, which exert protective effects against cardiac hypertrophy, heart failure and myocardial ischemia-reperfusion injury ( 36 – 39 ). Therefore, a pharmacologic agent to activate Sirt3 may have beneficial effects on cisplatin-induced renal injury.…”

Section: Discussionmentioning

confidence: 99%

Absence of Sirt3 aggravates cisplatin nephrotoxicity via enhanced renal tubular apoptosis and inflammation

et al. 2018

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Cisplatin-based chemotherapy is commonly used in the treatment of solid tumors; however, this agent is limited by its adverse effects on normal tissues, including the kidneys, ears and peripheral nerves. Mechanisms of cisplatin nephrotoxicity are proposed to involve oxidative stress, inflammation, cellular apoptosis and cell cycle regulation. Sirtuin 3 (Sirt3) is a member of the sirtuin family of NAD+-dependent enzymes with homology to Saccharomyces cerevisiae gene silent information regulator 2. Sirt3 is located in mitochondria and is involved in mitochondrial energy metabolism and function; however, the role of Sirt3 in cisplatin nephrotoxicity remains unclear. In the present study, whether Sirt3 has anti-inflammatory and anti-apoptotic effects on cisplatin-induced nephrotoxicity was investigated in mice. Sirt3 knockout mice (Sirt3(−/−)) and corresponding wild type mice were employed in the present study. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin (20 mg/kg). After 3 days following cisplatin treatment, blood and kidney tissues were harvested. Renal function and histology were evaluated. Tubular apoptosis, cell adhesion molecule expression, and inflammatory cells were evaluated by immunohistochemistry and western blot analysis. Following the induction of cisplatin nephrotoxicity, renal function was significantly aggravated in Sirt3 knockout (KO) mice. Tubular injury and inflammatory cell infiltration were significantly increased in Sirt3KO mice compared with wild type mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end label-positive tubular cells and renal monocyte chemoattractant protein-1 expression levels were increased in Sirt3KO mice compared with in wild type mice. In summary, the absence of Sirt3 aggravated in renal injury by increasing renal inflammation and tubular apoptosis. The results of the present study suggested that Sirt3 may have an important role in cisplatin-induced nephrotoxicity.

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“…Honokiol [(3’,5-di-(2-propenyl)-1,1’-biphenyl-2,2’-diol] is a natural biphenolic compound derived from an extract of seed cones and the bark of magnolia trees with anti-oxidative, anti-inflammatory and anti-tumor properties (Fried and Arbiser, 2009). Several mechanisms of honokiol have suggested that it maybe be a promising anticancer agent (Averett et al, 2014), such as the inhibition of STAT3 phosphorylation and the metastases in lung cancer cells (Pan et al, 2017), as well as the suppression of the development and progression of lung tumorigenesis by deregulating EGFR and its downstream effectors (Song et al, 2016). Honokiol also activated AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibited breast carcinogenesis (Nagalingam et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Honokiol Induces Apoptosis, G1 Arrest, and Autophagy in KRAS Mutant Lung Cancer Cells

Luo

Liu

et al. 2017

Front. Pharmacol.

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Aberrant signaling transduction induced by mutant KRAS proteins occurs in 20∼30% of non-small cell lung cancer (NSCLC), however, a direct and effective pharmacological inhibitor targeting KRAS has not yet reached the clinic to date. Honokiol, a small molecular polyphenol natural biophenolic compound derived from the bark of magnolia trees, exerts anticancer activity, however, its mechanism remains unknown. In this study, we sought to investigate the in vitro effects of honokiol on NSCLC cell lines harboring KRAS mutations. Honokiol was shown to induce G1 arrest and apoptosis to inhibit the growth of KRAS mutant lung cancer cells, which was weakened by an autophagy inhibitor 3-methyladenine (3-MA), suggesting a pro-apoptotic role of honokiol-induced autophagy that was dependent on AMPK-mTOR signaling pathway. In addition, we also discovered that Sirt3 was significantly up-regulated in honokiol treated KRAS mutant lung cancer cells, leading to destabilization of its target gene Hif-1α, which indicated that the anticancer property of honokiol maybe regulated via a novel mechanism associated with the Sirt3/Hif-1α. Taken together, these results broaden our understanding of the mechanisms on honokiol effects in lung cancer, and reinforce the possibility of its potential anticancer benefit as a popular Chinese herbal medicine (CHM).

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Molecular Targets of Honokiol

Cited by 16 publications

References 76 publications

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

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

Absence of Sirt3 aggravates cisplatin nephrotoxicity via enhanced renal tubular apoptosis and inflammation

Honokiol Induces Apoptosis, G1 Arrest, and Autophagy in KRAS Mutant Lung Cancer Cells

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