Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Must- Read Articles
      • "Best of" Collection
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Prevention Research
Cancer Prevention Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Must- Read Articles
      • "Best of" Collection
      • Editors' Picks
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Letter to the Editor

Targeting Apoptosis Pathways in Cancer—Letter

Stephen Safe
Stephen Safe
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: ssafe@cvm.tamu.edu
DOI: 10.1158/1940-6207.CAPR-14-0405 Published April 2015
  • Article
  • Info & Metrics
  • PDF
Loading

The review article entitled “Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature” (1) provides a comprehensive listing of the effects of natural products on genes/pathways that result in induction of apoptosis in cancer cells and tumors. Despite the multiple cancer cell context-dependent effects of natural products, the lack of underlying mechanisms of action for many compounds has limited their clinical applications and use in combined therapies. However, there are relevant mechanistic studies for some classes of natural products that were not covered in this review. For example, the authors have summarized the effects of various proapoptotic agents that act through two interrelated pathways, namely “mitochondrial-mediated” and “reactive oxygen species (ROS)-mediated” apoptosis because drugs targeting mitochondria often induce ROS. Previous studies in this laboratory have demonstrated that natural products such as curcumin, betulinic acid, phenethyl isothiocyanate (PEITC), piperlongumine, and celastrol, which induce ROS and apoptosis, also downregulate specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, which are highly expressed in cancer cells (2–6). For most of these studies, compound-induced apoptosis and compound-induced downregulation of Sp transcription factors were reversed in cancer cells after cotreatment with antioxidants. The importance of Sp transcription factors as targets for proapoptotic natural products is due to Sp-regulated prosurvival genes such as survivin and bcl-2, which are also downregulated by ROS-inducing anticancer agents (2–6).

The high expression of Sp transcription factors in cancer cells is due, in part, to suppression of the transcriptional (Sp) repressors ZBTB10/ZBTB34 and ZBTB4 by microRNA-27a (miR-27a) and miR-20a/miR-17-5p, respectively (6–8). These microRNAs are members of the miR-23a∼27a∼24-2 and miR-17-92 clusters, which are overexpressed in multiple cancer cells and tumors. The key mechanistic linkage between induction of ROS and modulation of the miR:ZBTB:Sp axis was initially reported in studies showing that, in colon cancer cells, hydrogen peroxide induced genome-wide shifts of repressor complexes from non–GC-rich to GC-rich promoters, and this downregulated expression of the oncogene cMyc. Our recent studies showed that PEITC also decreased expression of Myc in pancreatic cancer cells (ROS-dependent), resulting in decreased expression of Myc-regulated miR-27a and miR-20a/miR-17-5p, induction of ZBTBs, and downregulation of Sp transcription factors and prosurvival Sp-regulated genes (8). Further evidence that ROS targets Sp transcription factors and Sp-regulated survival genes has been observed in other studies using hydrogen peroxide, pharmacologic concentrations of ascorbic acid that induce hydrogen peroxide, t-butyl hydroperoxide, and other ROS-inducing anticancer agents. These studies provide some understanding of the underlying mechanisms of action that contribute to the proapoptotic effects of ROS-inducing natural products reviewed by Millimouno and colleagues in Cancer Prevention Research (1).

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

  • Received November 12, 2014.
  • Accepted January 22, 2015.
  • ©2015 American Association for Cancer Research.

References

  1. 1.↵
    1. Millimouno FM,
    2. Dong J,
    3. Yang L,
    4. Li J,
    5. Li X
    . Targeting apoptosis pathways in cancer and perspectives with natural compounds from Mother Nature. Cancer Prev Res 2014;7:1081–107.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Chadalapaka G,
    2. Jutooru I,
    3. Safe S
    . Celastrol decreases specificity proteins (Sp) and fibroblast growth factor receptor-3 (FGFR3) in bladder cancer cells. Carcinogenesis 2012;33:886–94.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Chintharlapalli S,
    2. Papineni S,
    3. Lei P,
    4. Pathi S,
    5. Safe S
    . Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer 2011;11:371.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Jutooru I,
    2. Chadalapaka G,
    3. Lei P,
    4. Safe S
    . Inhibition of NFkappaB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. J Biol Chem 2010;285:25332–44.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Gandhy SU,
    2. Kim K,
    3. Larsen L,
    4. Rosengren RJ,
    5. Safe S
    . Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity protein (Sp) transcription factors by targeting microRNAs. BMC Cancer 2012;12:564.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Jutooru I,
    2. Guthrie AS,
    3. Chadalapaka G,
    4. Pathi S,
    5. Kim K,
    6. Burghardt R,
    7. et al.
    Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents. Mol Cell Biol 2014;34:2382–95.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Mertens-Talcott SU,
    2. Chintharlapalli S,
    3. Li X,
    4. Safe S
    . The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Res 2007;67:11001–11.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Kim K,
    2. Chadalapaka G,
    3. Lee SO,
    4. Yamada D,
    5. Sastre-Garau X,
    6. Defossez PA,
    7. et al.
    Identification of oncogenic microRNA-17-92/ZBTB4/specificity protein axis in breast cancer. Oncogene 2012;31:1034–44.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
Cancer Prevention Research: 8 (4)
April 2015
Volume 8, Issue 4
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Prevention Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Targeting Apoptosis Pathways in Cancer—Letter
(Your Name) has forwarded a page to you from Cancer Prevention Research
(Your Name) thought you would be interested in this article in Cancer Prevention Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Targeting Apoptosis Pathways in Cancer—Letter
Stephen Safe
Cancer Prev Res April 1 2015 (8) (4) 338; DOI: 10.1158/1940-6207.CAPR-14-0405

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Targeting Apoptosis Pathways in Cancer—Letter
Stephen Safe
Cancer Prev Res April 1 2015 (8) (4) 338; DOI: 10.1158/1940-6207.CAPR-14-0405
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Disclosure of Potential Conflicts of Interest
    • References
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • HER2 Expression in NF1 Breast Cancer—Response
  • NF1 Alterations are Linked to Increased HER2 Expression in Breast Cancer–Letter
  • PDE5A Gene and Colon Cancer
Show more Letter to the Editor
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • Online First
  • Current Issue
  • Past Issues

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Prevention Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Prevention Research
eISSN: 1940-6215
ISSN: 1940-6207

Advertisement