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Coupling endoplasmic reticulum stress to the cell death program in mouse melanoma cells: effect of curcumin

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Abstract

The microenvironment of cancerous cells includes endoplasmic reticulum (ER) stress the resistance to which is required for the survival and growth of tumors. Acute ER stress triggers the induction of a family of ER stress proteins that promotes survival and/or growth of the cancer cells, and also confers resistance to radiation and chemotherapy. Prolonged or severe ER stress, however, may ultimately overwhelm the cellular protective mechanisms, triggering cell death through specific programmed cell death (pcd) pathways. Thus, downregulation of the protective stress proteins may offer a new therapeutic approach to cancer treatment. In this regard, recent reports have demonstrated the roles of the phytochemical curcumin in the inhibition of proteasomal activity and triggering the accumulation of cytosolic Ca2+ by inhibiting the Ca2+-ATPase pump, both of which enhance ER stress. Using a mouse melanoma cell line, we investigated the possibility that curcumin may trigger ER stress leading to programmed cell death. Our studies demonstrate that curcumin triggers ER stress and the activation of specific cell death pathways that feature caspase cleavage and activation, p23 cleavage, and downregulation of the anti-apoptotic Mcl-1 protein.

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Abbreviations

ER:

Endoplasmic reticulum

pcd:

Programmed cell death

eIF2α:

Eukaryotic initiation factor-2 alpha

GRP:

Glucose regulated protein

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Acknowledgements

We thank members of the Bredesen laboratory for helpful comments and discussions and Molly Susag for administrative assistance. This work was supported by grants from the National Institutes of Health (NS33376 to D.E.B. & R.V.R, AG12282 and NS45093 to D.E.B) and Elisabeth R. Levy and Family Foundation award.

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Authors and Affiliations

  1. Terra Linda High School, 320 Nova Albion Way, San Rafael, CA, 94903, USA

    Jason Bakhshi

  2. Undergraduate Program, University of California, 2200 University Ave, Berkeley, CA, 94720, USA

    Lee Weinstein

  3. The Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA, 94945, USA

    Karen S. Poksay, Dale E. Bredesen & Rammohan V. Rao

  4. Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Brian Nishinaga

  5. University of California, San Francisco, CA, 94143, USA

    Dale E. Bredesen

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  1. Jason Bakhshi
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  2. Lee Weinstein
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Correspondence to Rammohan V. Rao.

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Bakhshi, J., Weinstein, L., Poksay, K.S. et al. Coupling endoplasmic reticulum stress to the cell death program in mouse melanoma cells: effect of curcumin. Apoptosis 13, 904–914 (2008). https://doi.org/10.1007/s10495-008-0221-x

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