Prof. Sarit Larisch: Cancer Program: Targeting Cancer and Cancer Stem Cells using ARTS-based therapy
Main Researcher: Prof. Sarit Larisch
All cells in our body have the ability to self-destruct by activating an intrinsic cell suicide program called “Apoptosis”. In this way, the accumulation of damaged and potentially dangerous cells, such as tumor cells, is greatly limited.
Unfortunately, cancer cells can acquire resistance towards cell death by inactivating cell suicide pathways, thereby gaining the ability for “unlimited” life and propagation. However, the ability to undergo apoptosis is not completely lost in cancer cells and most currently used anti-cancer therapies (chemotherapy, radiation) act by activation this apoptosis death pathway in cancer cells.
Prof. Sarit Larisch's lab focuses on investigating the molecular mechanisms of cell death, and how abnormal regulation of this process contributes to human diseases. She identified a mitochondrial pro-apoptotic protein termed ARTS (Sept4_i2) that is derived from the Sept4 septin gene by differential splicing.
Over-expression of ARTS is sufficient to promote apoptosis in many cultured tumor cells.
Conversely, the reduction of endogenous ARTS protein by anti-sense or shRNA methods can protect cells against various pro-apoptotic insults.
This indicates that ARTS is important for induction of apoptosis in a wide variety of apoptosis paradigms. A central step for the execution of apoptosis is the activation of caspases, a family of enzymes that when activated bring about the demise of the cell. Caspases are regulated by both activators and inhibitors, such as IAPs (Inhibitor of Apoptosis Proteins).
The best characterized member of this family is X-IAP (X-linked IAP). ARTS is located at the mitochondrial outer membrane (MOM) in living cells, but in response to pro-apoptotic stimuli it translocates to the cytosol. This permits ARTS to bind and inhibit XIAP, thereby initiating caspase activation and apoptosis.
An important step in mitochondrial apoptosis is the release of Cytochrome C, and SMAC, which reside in the intermembrane space (IMS) of mitochondriato the cytosol. This requires opening of pores at the mitochondrial outer membrane (MOM), a process termed MOMP (Mitochondrial Outer Membrane Permeabilization). They have recently shown that ARTS initiates caspase activation upstream of MOMP. ARTS is localized at the outer membrane of mitochondria (MOM).
Following induction of apoptosis, ARTS rapidly translocates to the cytosol in a caspase-independent manner, where it binds XIAP. The translocation of ARTS from mitochondria occurs within minutes following apoptotic stimuli and precedes MOMP and the release of cytoC and SMAC seen hours after induction of apoptosis. Moreover, knockdown of ARTS strongly inhibits the release of SMAC and cytoC, suggesting that ARTS is required for the proper timing of MOMP and the release of these proteins (Edison et al. 2012).
ARTS expression is frequently lost in Acute Lymphoblastic Leukemia (ALL) and in lymphoma patients, indicating that ARTS functions as a tumor-suppressor protein. Furthermore, Sept4/ARTS-null mice exhibit spontaneous tumors and show accelerated tumor development in an Eu-Myc background. In addition, Sept4/ARTS-null mice display increased numbers of stem and progenitor cells, elevated XIAP protein and increased resistance to cell death. Taken together, these results firmly establish the physiological role of ARTS as an XIAP antagonist and a tumor suppressor protein.
Prof. Larisch's lab currently focuses on investigating the following :
1. Molecular mechanism of ARTS-induced apoptosis. Our goal is to determine how the binding of ARTS to IAPs (Inhibitor of Apoptosis Proteins) and other apoptotic regulators causes caspase activation and cell death.
2. Role of ARTS as a tumor suppressor in a wide variety of cancer models.
3. Develop in vitro and cell-based assays for identification and screening of small-molecule ARTS- mimetics that will selectively kill cancer cells and serve as anti-cancer drugs.
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