High endoplasmic reticulum activity renders Multiple myeloma cells hypersensitive to mitochondrial inhibitors

Metin Kurtoglu, Katherine Philips, Huaping Liu, Lawrence H. Boise, Theodore J. Lampidis

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Multiple myeloma (MM) cells continuously secrete large amounts of immunoglobulins that are folded in the endoplasmic reticulum (ER) whose function depend on the Ca2+ concentration inside its lumen. Recently, it was shown that the ER membrane leaks Ca2+ that is captured and delivered back by mitochondria in order to prevent its loss. Thus, we hypothesized that the highly active and abundant ER in MM cells results in greater Ca 2+-regulation by mitochondria which would render them sensitive to mitochondrial inhibitors. Here, we indeed find that Ca2+ leak is greater in 3 MM, when compared to 2 B-cell leukemia cell lines. Moreover, this greater leak in MM cells is associated with hypersensitivity to various mitochondrial inhibitors, including CCCP. Consistent with our hypothesis, CCCP is more potent in inducing the unfolded protein response marker, CHOP/GADD153 in MM versus B-cell leukemia lines. Additionally, MM cells are found to be significantly more sensitive to clinically used fenofibrate and troglitazone, both of which were recently shown to have inhibitory effects on mitochondrial function. Overall, our results demonstrate that the unusually high ER activity in MM cells may be exploited for therapeutic benefit through the use of mitochondrial inhibitors including troglitazone and fenofibrate.

Original languageEnglish (US)
Pages (from-to)129-140
Number of pages12
JournalCancer Chemotherapy And Pharmacology
Volume66
Issue number1
DOIs
StatePublished - May 2010

Keywords

  • Calcium
  • Fenofibrate
  • Mitochondria
  • Multiple myeloma
  • Troglitazone
  • Unfolded protein response

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

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