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Geldanamycin and its anti-cancer activities
Yayoi Fukuyo1, Clayton R Hunt, Nobuo Horikoshi
1Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States.
Abstract:
Geldanamycin is a benzoquinone ansamycin antibiotic that manifests anti-cancer activity through the inhibition of HSP90-chaperone function. The HSP90 molecular chaperone is expressed at high levels in a wide variety of human cancers including melanoma, leukemia, and cancers in colon, prostate, lung, and breast. In cancer cells dependent upon mutated and/or over-expressed oncogene proteins, HSP90 is thought to have a critical role in regulating the stability, folding, and activity of HSP90-associated proteins, so-called "client proteins". These client proteins include the growth-stimulating proteins and kinases that support malignant transformation. Recently, oncogenic activating BRAF mutants have been identified in variety of cancers where constitutive activation of the MEK/ERK MAPK signaling pathway is the key for tumorigenesis, and they have been shown to be client proteins for HSP90. Accordingly, HSP90 inhibition can suppress certain cancer-causing client proteins and therefore represents an important therapeutic target. The molecular mechanism underlying the anti-cancer effect of HSP90 inhibition is complicated. Geldanamycin and its derivatives have been shown to induce the depletion of mutationally-activated BRAF through several mechanisms. In this review, we will describe the HSP90-inhibitory mechanism, focusing on recent progress in understanding HSP90 chaperone structure-function relationships, the identification of new HSP90 client proteins and the development of HSP90 inhibitors for clinical applications.
Insights
Geldanamycin, an antibiotic, targets HSP90 (heat shock protein 90) to inhibit cancer cell growth. By blocking HSP90, it degrades key cancer-driving proteins like BRAF, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HSP90 (heat shock protein 90) is a molecular chaperone overexpressed in various human cancers.
- HSP90 stabilizes mutated or overexpressed oncoproteins, termed "client proteins," crucial for cancer cell survival and proliferation.
- Oncogenic BRAF mutants, key drivers of tumorigenesis via MAPK signaling, are identified as HSP90 client proteins.
Purpose of the Study:
- To elucidate the anti-cancer mechanisms of HSP90 inhibition by geldanamycin.
- To review recent advancements in understanding HSP90 chaperone structure-function relationships.
- To highlight the identification of novel HSP90 client proteins and the development of HSP90 inhibitors for clinical use.
Main Methods:
- Review of existing literature on geldanamycin and HSP90 inhibition.
- Analysis of HSP90 chaperone structure-function relationships.
- Examination of studies identifying HSP90 client proteins and clinical trials of HSP90 inhibitors.
Main Results:
- Geldanamycin inhibits HSP90 chaperone function, leading to anti-cancer activity.
- HSP90 inhibition results in the depletion of oncogenic client proteins, including mutationally activated BRAF.
- Recent research has expanded the understanding of HSP90's role and identified new therapeutic targets.
Conclusions:
- HSP90 inhibition is a validated therapeutic strategy against cancers dependent on HSP90 client proteins.
- Geldanamycin and its derivatives demonstrate potential in degrading key oncoproteins like BRAF.
- Further development of HSP90 inhibitors holds promise for clinical cancer treatment.
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