Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis
Takehiko Dohi1, Elena Beltrami, Nathan R Wall
1Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Abstract:
Evasion of apoptosis is a hallmark of cancer, but the molecular circuitries of this process are not understood. Here we show that survivin, a member of the inhibitor of apoptosis gene family that is overexpressed in cancer, exists in a novel mitochondrial pool in tumor cells. In response to cell death stimulation, mitochondrial survivin is rapidly discharged in the cytosol, where it prevents caspase activation and inhibits apoptosis. Selective targeting of survivin to mitochondria enhances colony formation in soft agar, accelerates tumor growth in immunocompromised animals, and abolishes tumor cell apoptosis in vivo. Therefore, mitochondrial survivin orchestrates a novel pathway of apoptosis inhibition, which contributes to tumor progression.
Insights
Survivin, a cancer-overexpressed protein, resides in mitochondria and inhibits apoptosis. Targeting survivin to mitochondria promotes tumor growth and prevents cancer cell death, revealing a novel apoptosis evasion pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Evasion of apoptosis is a critical hallmark of cancer.
- The precise molecular mechanisms underlying apoptosis evasion remain incompletely understood.
- Survivin, an inhibitor of apoptosis protein, is frequently overexpressed in various cancers.
Purpose of the Study:
- To elucidate the role of survivin in apoptosis evasion within cancer cells.
- To investigate the subcellular localization and function of survivin in tumor progression.
- To identify novel molecular pathways involved in cancer cell survival.
Main Methods:
- Utilized molecular biology techniques to study survivin localization in tumor cells.
- Investigated survivin's role in apoptosis signaling pathways upon cell death stimulation.
- Employed in vivo models (immunocompromised animals) to assess the impact of survivin targeting on tumor growth and apoptosis.
Main Results:
- Identified a novel mitochondrial pool of survivin in tumor cells.
- Demonstrated that mitochondrial survivin is released into the cytosol upon cell death stimuli.
- Showcased that survivin release inhibits caspase activation, thereby preventing apoptosis.
- Selective mitochondrial targeting of survivin enhanced colony formation and tumor growth in vivo.
- Observed abolished tumor cell apoptosis in vivo with targeted survivin.
Conclusions:
- Mitochondrial survivin plays a crucial role in orchestrating a novel pathway for apoptosis inhibition.
- This mitochondrial survivin pathway significantly contributes to cancer progression and tumor survival.
- Targeting this pathway presents a potential therapeutic strategy for cancer treatment.
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