Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma

Vijay Ramakrishnan, U. Painuly, T. Kimlinger, J. Haug, S Vincent Rajkumar, Shaji K Kumar

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The inhibitor of apoptosis (IAP) proteins have a critical role in the control of apoptotic machinery, and has been explored as a therapeutic target. Here, we have examined the functional importance of IAPs in multiple myeloma (MM) by using a Smac (second mitochondria-derived activator of caspases)-mimetic LCL161. We observed that LCL161 was able to potently induce apoptosis in some MM cell lines but not in others. Examining the levels of X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2) post LCL161 treatment indicated clear downregulation of both XIAP activity and cIAP1 levels in both the sensitive and less sensitive (resistant) cell lines. cIAP2, however, was not downregulated in the cell line resistant to the drug. Small interfering RNA-mediated silencing of cIAP2 significantly enhanced the effect of LCL161, indicating the importance of downregulation of all IAPs simultaneously for induction of apoptosis in MM cells. LCL161 induced marked up regulation of the Jak2/Stat3 pathway in the resistant MM cell lines. Combining LCL161 with a Jak2-specific inhibitor resulted in synergistic cell death in MM cell lines and patient cells. In addition, combining LCL161 with death-inducing ligands clearly showed that LCL161 sensitized MM cells to both Fas-ligand and TRAIL.

Original languageEnglish (US)
Pages (from-to)1519-1528
Number of pages10
JournalLeukemia
Volume28
Issue number7
DOIs
StatePublished - 2014

Fingerprint

Inhibitor of Apoptosis Proteins
Multiple Myeloma
Cell Line
X-Linked Inhibitor of Apoptosis Protein
Down-Regulation
Therapeutics
Apoptosis
Fas Ligand Protein
LCL161
Caspases
RNA Interference
Small Interfering RNA
Mitochondria
Cell Death
Up-Regulation
Ligands

Keywords

  • apoptosis
  • IAP
  • myeloma
  • Smac mimetic

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma. / Ramakrishnan, Vijay; Painuly, U.; Kimlinger, T.; Haug, J.; Rajkumar, S Vincent; Kumar, Shaji K.

In: Leukemia, Vol. 28, No. 7, 2014, p. 1519-1528.

Research output: Contribution to journalArticle

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