3,3’-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2

Xueli Tian, Kang Dong Liu, Xueyin Zu, Fayang Ma, Zhi Li, Mee Hyun Lee, Hanyong Chen, Yan Li, Yuzhou Zhao, Fangfang Liu, Naomi Oi, Ann M. Bode, Zigang Dong, Dong Joon Kim

Research output: Contribution to journalArticle

Abstract

3,3’-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.

Original languageEnglish (US)
Pages (from-to)20-30
Number of pages11
JournalCancer Letters
Volume448
DOIs
StatePublished - Apr 28 2019

Fingerprint

Heterografts
Colon
Growth
Neoplasms
Colonic Neoplasms
Brassica
Proteins
Phosphotransferases
diindolylmethane
3,3-diindolymethane
Growth Inhibitors
Enzyme Assays
Dinoprostone
Oral Administration
Drug Therapy

Keywords

  • Colon cancer
  • COX1/2
  • DIM
  • ERK1/2
  • Patient-derived xenograft

PubMed: MeSH publication types

  • Journal Article

Cite this

3,3’-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2. / Tian, Xueli; Liu, Kang Dong; Zu, Xueyin; Ma, Fayang; Li, Zhi; Lee, Mee Hyun; Chen, Hanyong; Li, Yan; Zhao, Yuzhou; Liu, Fangfang; Oi, Naomi; Bode, Ann M.; Dong, Zigang; Kim, Dong Joon.

In: Cancer Letters, Vol. 448, 28.04.2019, p. 20-30.

Research output: Contribution to journalArticle

Tian, Xueli ; Liu, Kang Dong ; Zu, Xueyin ; Ma, Fayang ; Li, Zhi ; Lee, Mee Hyun ; Chen, Hanyong ; Li, Yan ; Zhao, Yuzhou ; Liu, Fangfang ; Oi, Naomi ; Bode, Ann M. ; Dong, Zigang ; Kim, Dong Joon. / 3,3’-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2. In: Cancer Letters. 2019 ; Vol. 448. pp. 20-30.
@article{9117aeb9bacd4982a75eca94995449e8,
title = "3,3’-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2",
abstract = "3,3’-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.",
keywords = "Colon cancer, COX1/2, DIM, ERK1/2, Patient-derived xenograft",
author = "Xueli Tian and Liu, {Kang Dong} and Xueyin Zu and Fayang Ma and Zhi Li and Lee, {Mee Hyun} and Hanyong Chen and Yan Li and Yuzhou Zhao and Fangfang Liu and Naomi Oi and Bode, {Ann M.} and Zigang Dong and Kim, {Dong Joon}",
year = "2019",
month = "4",
day = "28",
doi = "10.1016/j.canlet.2019.01.031",
language = "English (US)",
volume = "448",
pages = "20--30",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - 3,3’-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2

AU - Tian, Xueli

AU - Liu, Kang Dong

AU - Zu, Xueyin

AU - Ma, Fayang

AU - Li, Zhi

AU - Lee, Mee Hyun

AU - Chen, Hanyong

AU - Li, Yan

AU - Zhao, Yuzhou

AU - Liu, Fangfang

AU - Oi, Naomi

AU - Bode, Ann M.

AU - Dong, Zigang

AU - Kim, Dong Joon

PY - 2019/4/28

Y1 - 2019/4/28

N2 - 3,3’-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.

AB - 3,3’-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.

KW - Colon cancer

KW - COX1/2

KW - DIM

KW - ERK1/2

KW - Patient-derived xenograft

UR - http://www.scopus.com/inward/record.url?scp=85061333753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061333753&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2019.01.031

DO - 10.1016/j.canlet.2019.01.031

M3 - Article

VL - 448

SP - 20

EP - 30

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -