Oncotarget

Research Papers:

A novel curcumin analog inhibits canonical and non-canonical functions of telomerase through STAT3 and NF-κB inactivation in colorectal cancer cells

Seyung S. Chung _, Pranabananda Dutta, Nathaniel Chard, Yong Wu, Qiao-Hong Chen, Guanglin Chen and Jaydutt Vadgama _

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Oncotarget. 2019; 10:4516-4531. https://doi.org/10.18632/oncotarget.27000

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Abstract

Seyung S. Chung1,4, Pranabananda Dutta1, Nathaniel Chard1, Yong Wu1,4, Qiao-Hong Chen3, Guanglin Chen3 and Jaydutt Vadgama1,2,4

1 Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059, USA

2 Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, USA

3 Department of Chemistry, California State University at Fresno, Fresno, California 93740, USA

4 David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA

Correspondence to:

Seyung S. Chung,email: seyungchung@cdrewu.edu
Jaydutt Vadgama,email: jayvadgama@cdrewu.edu

Keywords: curcumin analog; cancer stem cells; colorectal cancer; STAT3; NF-κB

Abbreviations: CRC: colorectal cancer; CSC: cancer stem cell; STAT3: signal transducer and activator of transcription 3; NF-κB: nuclear factor κB; hTERT: human telomerase reverse transcriptase

Received: March 05, 2019     Accepted: May 20, 2019     Published: July 16, 2019

ABSTRACT

Curcumin is a biologically active polyphenol that exists in Indian spice turmeric. It has been reported that curcumin exerted anti-inflammatory, anti-oxidant and anti-cancer effects in numerous in vitro and in vivo studies. However, it is not well-understood the molecular mechanism of curcumin for the cancer stem cells and telomerase in colorectal cancer. In this study, compound 19, a nitrogen-containing curcumin analog, was used to treat human colorectal cancer cells. Compound 19 showed a greater anti-proliferative activity than curcumin while displayed no significant toxicity toward normal human colon epithelial cells. Compound 19 exerted anti-inflammatory activities by deactivating STAT3 and NF-κB. In cancer stem cell populations, CD44, Oct-4 and ALDHA1 expressions were abolished upon treating with compound 19. Cancer stem cell biomarkers CD51 and CD133 positive populations were reduced and telomerase activities were decreased with the reduced STAT3 binding to hTERT promoters. This means compound 19 dually inhibits canonical and non-canonical functions of telomerase. Furthermore, compound 19 treatments induced cell cycle arrest at G1 phase and apoptosis. Human apoptosis-related array screening revealed that activated caspase 3, catalase, clusterin and cytochrome C led to apoptosis. Taken together, our data suggest that compound 19 can be a novel therapeutic agent for metastatic colorectal cancer by concurrently targeting STAT3 and NF-κB signaling pathways.


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