Bibliographic Details
| Title: |
PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity. |
| Authors: |
Varuzhanyan, Grigor, Chia-Chun Chen, Freeland, Jack, Tian He, Tran, Wendy, Kai Song, Liang Wang, Donghui Cheng, Shili Xu, Dibernardo, Gabriella A., Esedebe, Favour N., Bhatia, Vipul, Mingqi Han, Abt, Evan R., Jung Wook Park, Memarzadeh, Sanaz, Shackelford, David B., Lee, John K., Graeber, Thomas G., Shirihai, Orian S. |
| Source: |
Proceedings of the National Academy of Sciences of the United States of America; 12/3/2024, Vol. 121 Issue 49, p1-29, 53p |
| Subject Terms: |
POSITRON emission tomography, NEUROENDOCRINE cells, OXIDATIVE phosphorylation, PROSTATE tumors, CANCER cells |
| Abstract: |
Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
