A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells

Ke Jia Wu; Jie Min Huang; Hai Jing Zhong; Zhen Zhen Dong; Kasipandi Vellaisamy; Jin Jian Lu; Xiu Ping Chen; Pauline Chiu; Daniel W J Kwong; Simon Q B Han; Edmond Dik Lung Ma; Chung Hang Leung

doi:10.1371/journal.pone.0177123

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells

Ke Jia Wu, Jie Min Huang, Hai Jing Zhong, Zhen Zhen Dong, Kasipandi Vellaisamy, Jin Jian Lu, Xiu Ping Chen, Pauline Chiu, Daniel W J Kwong, Simon Q B Han, Edmond Dik Lung Ma^*, Chung Hang Leung^*

^*Corresponding author for this work

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

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Abstract

The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the antiapoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

Original language	English
Article number	e0177123
Number of pages	12
Journal	PLoS ONE
Volume	12
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0177123
Publication status	Published - Jun 2017

Scopus Subject Areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
General

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10.1371/journal.pone.0177123

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@article{a1c55b1117d945a3a8eded8e3ecdaab3,

title = "A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells",

abstract = "The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the antiapoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.",

author = "Wu, {Ke Jia} and Huang, {Jie Min} and Zhong, {Hai Jing} and Dong, {Zhen Zhen} and Kasipandi Vellaisamy and Lu, {Jin Jian} and Chen, {Xiu Ping} and Pauline Chiu and Kwong, {Daniel W J} and Han, {Simon Q B} and Ma, {Edmond Dik Lung} and Leung, {Chung Hang}",

note = "Funding: This work is supported by Hong Kong Baptist University (FRG2/15-16/002), the Health and Medical Research Fund (HMRF/14130522), the Research Grants Council (HKBU/12301115, HKBU/204612 and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12 – Oligoswitch), National Natural Science Foundation of China (21575121), Guangdong Province Natural Science Foundation (2015A030313816), Hong Kong Baptist University Century Club Sponsorship Scheme 2016, Interdisciplinary Research Matching Scheme (RC-IRMS/15-16/03), the Science and Technology Development Fund, Macao SAR (098/2014/A2), the University of Macau (MYRG2015-00137-ICMS-QRCM, MYRG2016-00151-ICMS-QRCM and MRG044/LCH/2015/ICMS) to CHL, and National Natural Science Foundation of China (21628502).",

year = "2017",

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doi = "10.1371/journal.pone.0177123",

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AU - Wu, Ke Jia

AU - Huang, Jie Min

AU - Zhong, Hai Jing

AU - Dong, Zhen Zhen

AU - Vellaisamy, Kasipandi

AU - Lu, Jin Jian

AU - Chen, Xiu Ping

AU - Chiu, Pauline

AU - Kwong, Daniel W J

AU - Han, Simon Q B

AU - Ma, Edmond Dik Lung

AU - Leung, Chung Hang

N1 - Funding: This work is supported by Hong Kong Baptist University (FRG2/15-16/002), the Health and Medical Research Fund (HMRF/14130522), the Research Grants Council (HKBU/12301115, HKBU/204612 and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12 – Oligoswitch), National Natural Science Foundation of China (21575121), Guangdong Province Natural Science Foundation (2015A030313816), Hong Kong Baptist University Century Club Sponsorship Scheme 2016, Interdisciplinary Research Matching Scheme (RC-IRMS/15-16/03), the Science and Technology Development Fund, Macao SAR (098/2014/A2), the University of Macau (MYRG2015-00137-ICMS-QRCM, MYRG2016-00151-ICMS-QRCM and MRG044/LCH/2015/ICMS) to CHL, and National Natural Science Foundation of China (21628502).

PY - 2017/6

Y1 - 2017/6

N2 - The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the antiapoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

AB - The JAK2/STAT3 signaling pathway plays a critical role in tumorigenesis, and has been suggested as a potential molecular target for anti-melanoma therapeutics. However, few JAK2 inhibitors were being tested for melanoma therapy. In this study, eight amentoflavone analogues were evaluated for their activity against human malignant melanoma cells. The most potent analogue, compound 1, inhibited the phosphorylation of JAK2 and STAT3 in human melanoma cells, but had no discernible effect on total JAK2 and STAT3 levels. A cellular thermal shift assay was performed to identify that JAK2 is engaged by 1 in cell lysates. Moreover, compound 1 showed higher antiproliferative activity against human melanoma A375 cells compared to a panel of cancer and normal cell lines. Compound 1 also activated caspase-3 and cleaved PARP, which are markers of apoptosis, and suppressed the antiapoptotic Bcl-2 level. Finally, compound 1 induced apoptosis in 80% of treated melanoma cells. To our knowledge, compound 1 is the first amentoflavone-based JAK2 inhibitor to be investigated for use as an anti-melanoma agent.

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DO - 10.1371/journal.pone.0177123

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SN - 1932-6203

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JO - PLoS ONE

JF - PLoS ONE

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ER -

A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells

Abstract

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