Killing of human melanoma cells induced by activation of class I interferon-regulated signaling pathways via MDA-7/IL-24.
Restoration of the tumor-suppression function by gene transfer of the melanoma differentiation-associated gene 7 (MDA7)/interleukin 24 (IL-24) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/IL-24 treatment of melanoma cells down-regulates interferon regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1-regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN-alpha) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN (IFN-gamma), on the other hand, supports melanoma cell survival, possibly through constitutive activation of iNOS expression. We therefore conducted this study to explore the molecular pathways of MDA7/IL-24 regulation of apoptosis via the intracellular induction of IFNs in melanoma. We hypothesized that the restoration of the MDA7/IL-24 axis leads to upregulation of class I IFNs and induction of the apoptotic cascade. We found that MDA7/IL-24 induces the secretion of endogenous IFN-beta, another class I IFN, leading to the arrest of melanoma cell growth and apoptosis. We also identified a series of apoptotic markers that play a role in this pathway, including the regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-FasL. In summary, we described a novel pathway of MDA7/IL-24 regulation of apoptosis in melanoma tumors via endogenous IFN-beta induction followed by IRF regulation and TRAIL/FasL system activation.
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 362, Houston, TX 77030, USA. sekmekcioglu@mdanderson.org
Suhendan
S
Ekmekcioglu
John B
JB
Mumm
Malini
M
Udtha
Sunil
S
Chada
Elizabeth A
EA
Grimm
D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000502:physiology*; D007378:Interleukins / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D000099180:Interleukin-24
D016898:Interferon-alpha; D016899:Interferon-beta; D007378:Interleukins; D000099180:Interleukin-24