[6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2

Myoung Ok Kim; Mee Hyun Lee; Naomi Hamada; Sung Hyun Kim; KiBeom Bae; Zunnan Huang; Dong Joon Kim; Srinivasa Reddy Kanamata Reddy; Sung-Young Lee; Si Jun Park; Jae Young Kim; Hua Xie; Joydeb Kumar Kundu; Zae Young Ryoo; Ann M. Bode; Young Joon Surh; Zigang Dong

doi:10.1093/carcin/bgt365

[6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2

Myoung Ok Kim, Mee Hyun Lee, Naomi Hamada, Sung Hyun Kim, KiBeom Bae, Zunnan Huang, Dong Joon Kim, Srinivasa Reddy Kanamata Reddy, Sung-Young Lee, Si Jun Park, Jae Young Kim, Hua Xie, Joydeb Kumar Kundu, Zae Young Ryoo, Ann M. Bode, Young Joon Surh, Zigang Dong

Hormel Institute

Research output: Contribution to journal › Article › peer-review

77 Scopus citations

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascadesis considered to be a rational therapeutic and preventivestrategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components,including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclinD1/3, which are target proteins in the Akt signaling pathway.The induction of apoptosis in NCI-H1650 cells by [6]-shogaolcorresponded with the cleavage of caspase-3 and caspase-7.Moreover, intraperitoneal administration of [6]-shogaol inhibitedthe growth of NCI-H1650 cells as tumor xenografts in nudemice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC.

Original language	English (US)
Pages (from-to)	683-691
Number of pages	9
Journal	Carcinogenesis
Volume	35
Issue number	3
DOIs	https://doi.org/10.1093/carcin/bgt365
State	Published - Mar 2014

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Kim, M. O., Lee, M. H., Hamada, N., Kim, S. H., Bae, K., Huang, Z., Kim, D. J., Kanamata Reddy, S. R., Lee, S.-Y., Park, S. J., Kim, J. Y., Xie, H., Kundu, J. K., Ryoo, Z. Y., Bode, A. M., Surh, Y. J., & Dong, Z. (2014). [6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2. Carcinogenesis, 35(3), 683-691. https://doi.org/10.1093/carcin/bgt365

Kim, MO, Lee, MH, Hamada, N, Kim, SH, Bae, K, Huang, Z, Kim, DJ, Kanamata Reddy, SR, Lee, S-Y, Park, SJ, Kim, JY, Xie, H, Kundu, JK, Ryoo, ZY, Bode, AM, Surh, YJ & Dong, Z 2014, '[6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2', Carcinogenesis, vol. 35, no. 3, pp. 683-691. https://doi.org/10.1093/carcin/bgt365

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title = "[6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2",

abstract = "Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascadesis considered to be a rational therapeutic and preventivestrategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components,including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclinD1/3, which are target proteins in the Akt signaling pathway.The induction of apoptosis in NCI-H1650 cells by [6]-shogaolcorresponded with the cleavage of caspase-3 and caspase-7.Moreover, intraperitoneal administration of [6]-shogaol inhibitedthe growth of NCI-H1650 cells as tumor xenografts in nudemice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC.",

author = "Kim, {Myoung Ok} and Lee, {Mee Hyun} and Naomi Hamada and Kim, {Sung Hyun} and KiBeom Bae and Zunnan Huang and Kim, {Dong Joon} and {Kanamata Reddy}, {Srinivasa Reddy} and Sung-Young Lee and Park, {Si Jun} and Kim, {Jae Young} and Hua Xie and Kundu, {Joydeb Kumar} and Ryoo, {Zae Young} and Bode, {Ann M.} and Surh, {Young Joon} and Zigang Dong",

year = "2014",

month = mar,

doi = "10.1093/carcin/bgt365",

language = "English (US)",

volume = "35",

pages = "683--691",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "3",

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T1 - [6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2

AU - Kim, Myoung Ok

AU - Lee, Mee Hyun

AU - Hamada, Naomi

AU - Kim, Sung Hyun

AU - Bae, KiBeom

AU - Huang, Zunnan

AU - Kim, Dong Joon

AU - Kanamata Reddy, Srinivasa Reddy

AU - Lee, Sung-Young

AU - Park, Si Jun

AU - Kim, Jae Young

AU - Xie, Hua

AU - Kundu, Joydeb Kumar

AU - Ryoo, Zae Young

AU - Bode, Ann M.

AU - Surh, Young Joon

AU - Dong, Zigang

PY - 2014/3

Y1 - 2014/3

N2 - Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascadesis considered to be a rational therapeutic and preventivestrategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components,including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclinD1/3, which are target proteins in the Akt signaling pathway.The induction of apoptosis in NCI-H1650 cells by [6]-shogaolcorresponded with the cleavage of caspase-3 and caspase-7.Moreover, intraperitoneal administration of [6]-shogaol inhibitedthe growth of NCI-H1650 cells as tumor xenografts in nudemice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC.

AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Despite progress in developing chemotherapeutics for the treatment of NSCLC, primary and secondary resistance limits therapeutic success. NSCLC cells exhibit multiple mutations in the epidermal growth factor receptor (EGFR), which cause aberrant activation of diverse cell signaling pathways. Therefore, suppression of the inappropriate amplification of EGFR downstream signaling cascadesis considered to be a rational therapeutic and preventivestrategy for the management of NSCLC. Our initial molecular target-oriented virtual screening revealed that the ginger components,including [6]-shogaol, [6]-paradol and [6]-gingerol, seem to be potential candidates for the prevention and treatment of NSCLC. Among the compounds, [6]-shogaol showed the greatest inhibitory effects on the NSCLC cell proliferation and anchorage-independent growth. [6]-Shogaol induced cell cycle arrest (G1 or G2/M) and apoptosis. Furthermore, [6]-shogaol inhibited Akt kinase activity, a downstream mediator of EGFR signaling, by binding with an allosteric site of Akt. In NCI-H1650 lung cancer cells, [6]-shogaol reduced the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and decreased the expression of cyclinD1/3, which are target proteins in the Akt signaling pathway.The induction of apoptosis in NCI-H1650 cells by [6]-shogaolcorresponded with the cleavage of caspase-3 and caspase-7.Moreover, intraperitoneal administration of [6]-shogaol inhibitedthe growth of NCI-H1650 cells as tumor xenografts in nudemice. [6]-Shogaol suppressed the expression of Ki-67, cyclin D1 and phosphorylated Akt and STAT3 and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positivity in xenograft tumors. The current study clearly indicates that [6]-shogaol can be exploited for the prevention and/or treatment of NSCLC.

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[6]-Shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2

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