This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Savino, J. A. Articles by Carter, T. H. Search for Related Content PubMed PubMed Citation Articles by Savino, J. A., III Articles by Carter, T. H.

¹ Department of Biological Sciences, St. John's University, Jamaica, New York; ² Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York; and Department of Otolaryngology, Long Island Jewish Medical Center, the Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, New York

Requests for reprints: Timothy H. Carter, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030. Phone: 516-562-1187; Fax: 516-562-1022. E-mail: cartert{at}stjohns.edu

Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, causes growth arrest and apoptosis of cancer cells in vitro. DIM also induces endoplasmic reticulum (ER) stress, and thapsigargin, a specific inhibitor of the sarcoplasmic reticulum/ER calcium-dependent ATPase, enhances this effect. We asked whether elevated cytosolic free calcium [Ca²⁺]_i is required for cytotoxicity of DIM and thapsigargin in two cancer cells lines (C33A, from cervix, and DU145, from prostate). [Ca²⁺]_i was measured in real-time by FURA-2 fluorescence. We tested whether DIM, thapsigargin, and DIM + thapsigargin cause apoptosis, measured by nucleosome release, under conditions that prevented elevation of [Ca²⁺]_i, using both cell-permeable and cell-impermeable forms of the specific calcium chelator BAPTA. DIM, like thapsigargin, rapidly mobilized ER calcium. C33A and DU145 responded differently to perturbations in Ca²⁺ homeostasis, suggesting that DIM induces apoptosis by different mechanisms in these two cell lines and/or that calcium mobilization also activates different survival pathways in C33A and DU145. Apoptosis in C33A was independent of increased [Ca²⁺]_i, suggesting that depletion of ER Ca²⁺ stores may be sufficient for cell killing, whereas apoptosis in DU145 required elevated [Ca²⁺]_i for full response. Inhibitor studies using cyclosporin A and KN93 showed that Ca²⁺ signaling is important for cell survival but the characteristics of this response also differed in the two cell lines. Our results underscore the complex and variable nature of cellular responses to disrupted Ca²⁺ homeostasis and suggest that alteration Ca²⁺ homeostasis in the ER can induce cellular apoptosis by both calcium-dependent and calcium-independent mechanisms. [Mol Cancer Ther 2006;5(3):556–63]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Our unpublished results.

⁴ Unpublished data.

Received 9/ 6/05; revised 11/25/05; accepted 1/12/06.

This article has been cited by other articles:

				S. Ali, S. Banerjee, A. Ahmad, B. F. El-Rayes, P. A. Philip, and F. H. Sarkar Apoptosis-inducing effect of erlotinib is potentiated by 3,3'-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer Mol. Cancer Ther., June 1, 2008; 7(6): 1708 - 1719. [Abstract] [Full Text] [PDF]