BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis

Academic Article

Abstract

  • Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that induces cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers in cell culture and animal models. Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas. Despite intensive study the molecular basis of tumor-cell selectivity of mda-7/IL-24 is not well characterized. Using deletion analysis, a specific mutant of MDA-7/IL-24, M4, consisting of amino acids 104 to 206, is described that retains the cancer-specific growth-suppressive and apoptosis-inducing properties of the full-length protein. Employing rationally designed mutational analysis, we show that MDA-7/IL-24 and M4 physically interact with BiP/GRP78 through their C and F helices, localize in the endoplasmic reticulum, and activate p38 MAPK and GADD gene expression, culminating in cancer-selective apoptosis. These studies provide novel mechanistic insights into the discriminating antitumor activity of MDA-7/IL-24 by elucidating BiP/GKP78 as a defined intracellular target of action and present an unparalleled opportunity to develop improved therapeutic versions of this cancer-specific apoptosis-inducing cytokine. ©2006 American Association for Cancer Research.
  • Published In

  • Cancer Research  Journal
  • Digital Object Identifier (doi)

    Author List

  • Gupta P; Walter MR; Su ZZ; Lebedeva IV; Emdad L; Randolph A; Valerie K; Sarkar D; Fisher PB
  • Start Page

  • 8182
  • End Page

  • 8191
  • Volume

  • 66
  • Issue

  • 16