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Identification of the apoptosis activation cascade induced in mammary carcinomas by energy restriction

Henry J Thompson1, Zongjian Zhu, Weiqin Jiang

  • 1Cancer Prevention Laboratory, Colorado State University, 1173 Campus Delivery, Fort Collins, CO 80523, USA. henry.thompson@colostate.edu

Cancer Research
|February 20, 2004
PubMed

Insights

Energy restriction (ER) significantly reduces mammary tumor size by inducing apoptosis. This process involves the mitochondrial pathway, with decreased cell survival factors and reduced Akt phosphorylation, suggesting ER inhibits cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Energy restriction (ER) is known to inhibit mammary carcinogenesis and reduce tumor size.
  • The underlying mechanism is hypothesized to involve ER-mediated apoptosis induction.

Purpose of the Study:

  • To investigate the molecular mechanisms by which energy restriction induces apoptosis in mammary carcinomas.
  • To determine the reversibility of ER-mediated effects on apoptosis.

Main Methods:

  • Evaluation of chemically induced mammary carcinomas from rats under ad libitum feeding, 40% ER, and 40% ER with energy repletion (ER-REP).
  • Biochemical assays for cleaved poly(ADP-ribose) polymerase 1 (PARP-1) and caspase activities (caspase 9, 3, and 8).
  • cDNA microarray analysis to identify involved gene families and Western blotting for apoptosis-related proteins (Bcl-2, Bcl-xl, XIAP, Bax, Apaf-1) and Akt phosphorylation.

Main Results:

  • ER significantly increased cleaved PARP-1, indicating apoptosis induction.
  • Microarray analysis implicated Bcl-2, CARD, and IAP gene families.
  • Caspase 9 and 3 activities were elevated in ER carcinomas, while caspase 8 activity remained unchanged.
  • ER carcinomas showed lower levels of Bcl-2, Bcl-xl, and XIAP, and elevated levels of Bax and Apaf-1.
  • Akt phosphorylation was reduced in ER carcinomas.

Conclusions:

  • Energy restriction induces apoptosis in mammary carcinomas through the mitochondrial pathway.
  • ER downregulates pro-survival factors (Bcl-2, Bcl-xl, XIAP) and upregulates pro-apoptotic factors (Bax, Apaf-1).
  • ER-induced apoptosis is associated with reduced Akt activation, suggesting a cell survival factor-dependent pathway.

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