Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.

Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor, RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored a hypothesized inverse relationship between MDA-9 and RKIP in melanoma.

MDA-9/syntenin: a positive gatekeeper of melanoma metastasis.

Melanoma differentiation associated gene-9 (MDA-9), synonymous with syntenin, is an adapter protein that provides a central role in regulating cell-cell and cell-matrix adhesion. MDA-9/syntenin transduces signals from the cell-surface to the interior through its interaction with a plethora of additional proteins and actively participates in intracellular trafficking and cell-surface targeting, synaptic transmission, and axonal outgrowth. Recent studies demarcate a seminal role of MDA-9/syntenin in cancer metastasis.

Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity.

Aggressive tumor growth, diffuse tissue invasion, and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. Astrocyte elevated gene-1 (AEG-1) is an oncogene that is overexpressed in several types of human cancers, including more than 90% of brain tumors.

Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics.

Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft.

mda-7/IL-24 differentially regulates soluble and nuclear clusterin in prostate cancer.

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of anti-tumor immune responses. Here, we identify clusterin (CLU) as a MDA-7/IL-24 interacting protein in DU-145 cells and investigate the role of MDA-7/IL-24 in regulating CLU expression and mediating the antitumor properties of mda-7/IL-24 in prostate cancer. Ad.

Autophagy switches to apoptosis in prostate cancer cells infected with melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24).

MDA-7/IL-24 has noteworthy potential as an anticancer therapeutic because of its diversity of antitumor properties, its lack of toxicity toward normal cells and tissues, and its safety and efficacy as evidenced in a phase I clinical trial. In a recent study, we document that Ad.mda-7-induced ER stress and ceramide production leads to early autophagy that subsequently switches to apoptosis in human prostate cancer cells.

Developing an effective gene therapy for prostate cancer: New technologies with potential to translate from the laboratory into the clinic.

Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease.

Astrocyte elevated gene-1 induces protective autophagy.

Astrocyte-elevated gene-1 (AEG-1) expression increases in multiple cancers and plays a crucial role in oncogenic transformation and angiogenesis, which are essential components in tumor cell development, growth, and progression to metastasis. Moreover, AEG-1 directly contributes to resistance to chemotherapeutic drugs, another important hallmark of aggressive cancers. In the present study, we document that AEG-1 mediates protective autophagy, an important regulator of cancer survival under metabolic stress and resistance to apoptosis, which may underlie its significant cancer-promoting properties.

mda-7/IL-24: a unique member of the IL-10 gene family promoting cancer-targeted toxicity.

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that displays nearly ubiquitous cancer-specific toxicity, with no harmful effects toward normal cells or tissues. mda-7/IL-24 was cloned from human melanoma cells by differentiation induction subtraction hybridization (DISH) and promotes endoplasmic reticulum (ER) stress culminating in apoptosis or toxic autophagy in a broad-spectrum of human cancers, when assayed in cell culture, in vivo in human tumor xenograft mouse models and in a Phase I clinical trial in patients with advanced cancers. This therapeutically active cytokine also induces indirect antitumor activity through inhibition of angiogenesis, stimulation of an antitumor immune response, and sensitization of cancer cells to radiation-, chemotherapy- and antibody-induced killing.

The development of MDA-7/IL-24 as a cancer therapeutic.

The cytokine melanoma differentiation associated gene 7 (mda-7) was identified by subtractive hybridization as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to non-transformed cells. Based on conserved structure, chromosomal location and cytokine-like properties, MDA-7, was classified as a member of the interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have demonstrated that expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in corresponding equivalent non-transformed cells, causes their growth arrest and rapid cell death.

MDA-7/IL-24 as a cancer therapeutic: from bench to bedside.

The novel cytokine melanoma differentiation associated gene-7 (mda-7) was identified by subtractive hybridization in the mid-1990s as a protein whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared with non-transformed cells. On the basis of conserved structure, chromosomal location and cytokine-like properties, MDA-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as MDA-7/IL-24. Multiple studies have shown that the expression of MDA-7/IL-24 in a wide variety of tumor cell types, but not in the corresponding equivalent non-transformed cells, causes their growth arrest and ultimately cell death.

Human polynucleotide phosphorylase selectively and preferentially degrades microRNA-221 in human melanoma cells.

MicroRNAs (miRNA), small noncoding RNAs, affect a broad range of biological processes, including tumorigenesis, by targeting gene products that directly regulate cell growth. Human polynucleotide phosphorylase (hPNPase(old-35)), a type I IFN-inducible 3'-5' exoribonuclease, degrades specific mRNAs and small noncoding RNAs. The present study examined the effect of this enzyme on miRNA expression in human melanoma cells.

Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine.

Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a cytokine belonging to the IL-10 family, selectively induces apoptosis in cancer cells without harming normal cells by promoting an endoplasmic reticulum (ER) stress response. The precise molecular mechanism by which the ER stress response culminates in cell death requires further clarification. The present study shows that in prostate carcinoma cells, the mda-7/IL-24-induced ER stress response causes apoptosis by translational inhibition of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1).

Mechanism of autophagy to apoptosis switch triggered in prostate cancer cells by antitumor cytokine melanoma differentiation-associated gene 7/interleukin-24.

Melanoma differentiation-associated gene 7 (mda-7)/interleukin-24 (IL-24) is a unique member of the IL-10 gene family, which displays a broad range of antitumor properties, including induction of cancer-specific apoptosis. Adenoviral-mediated delivery by Ad.mda-7 invokes an endoplasmic reticulum (ER) stress response that is associated with ceramide production and autophagy in some cancer cells.

Molecular mechanism of chemoresistance by astrocyte elevated gene-1.

Our recent findings show that astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) samples, and AEG-1 plays a central role in regulating development and progression of HCC. In the present study, we elucidate a molecular mechanism of AEG-1-induced chemoresistance, an important characteristic of aggressive cancers. AEG-1 increases the expression of multidrug resistance gene 1 (MDR1) protein, resulting in increased efflux and decreased accumulation of doxorubicin, promoting doxorubicin resistance.

Astrocyte elevated gene-1: a novel target for human glioma therapy.

Malignant gliomas including glioblastoma multiforme (GBM) and anaplastic astrocytomas are the most common primary brain tumors. Despite multimodal treatment including surgery, chemotherapy, and radiation, median survival for patients with GBMs is only 12 to 15 months. Identifying molecules critical for glioma progression is crucial for devising effective targeted therapy.

Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis.

Astrocyte-elevated gene-1 (AEG-1) expression is increased in multiple cancers and plays a central role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Additionally, overexpression of AEG-1 protects primary and transformed human and rat cells from serum starvation-induced apoptosis through activation of PI3K/Akt signaling. These findings suggest, but do not prove, that AEG-1 may function as an oncogene.

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24.

A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells.

Mechanism of in vitro pancreatic cancer cell growth inhibition by melanoma differentiation-associated gene-7/interleukin-24 and perillyl alcohol.

The death rate for pancreatic cancer approximates the number of new cases each year, and when diagnosed, current therapeutic regimens provide little benefit in extending patient survival. These dire statistics necessitate the development of enhanced single or combinatorial therapies to decrease the pathogenesis of this invariably fatal disease. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a potent cancer gene therapeutic because of its broad-spectrum cancer-specific apoptosis-inducing properties as well as its multipronged indirect antitumor activities.

Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis.

Pancreatic cancer is one of the deadliest of cancers. Even with aggressive therapy, the 5-year survival rate is <5%, mandating development of more effective treatments. Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) shows potent antitumor activity against most cancers displaying safety with significant clinical efficacy.

Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes.

Glutamate is an essential neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters primarily expressed in astroglial cells. Dysfunction of EAAT2 is implicated in acute and chronic neurological disorders, including stroke/ischemia, temporal lobe epilepsy, amyotrophic lateral sclerosis, Alzheimer disease, human immunodeficiency virus 1-associated dementia, and growth of malignant gliomas.

Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter.

One impediment to effective cancer-specific gene therapy is the rarity of regulatory sequences targeting gene expression selectively in tumor cells. Although many tissue-specific promoters are recognized, few cancer-selective gene promoters are available. Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression.

mda-7/IL-24: exploiting cancer's Achilles' heel.

The mda-7/IL-24 cDNA was isolated almost a decade ago in a screen for genes differentially upregulated following growth arrest and terminal differentiation of a human melanoma cell line employed as an in vitro cell differentiation model. The underlying rationale for the screen was that oncogenesis arises from a cellular dedifferentiation process culminating in uncontrolled proliferation and acquisition of invasive and metastatic potential. Identification of genes upregulated during the process of reactivation of faulty or inoperational differentiation maintenance programs was postulated to have cancer gene therapeutic potential.

MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells.

We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability.