HSP90-stabilized proteins as therapeutic targets in cancer

by Luisa Klemke
Cumulative thesis
Date of Examination:2021-06-08
Date of issue:2021-06-25
Advisor:PD Dr. Ramona Schulz-Heddergott
Referee:PD Dr. Ramona Schulz-Heddergott
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Christian Brandts
Persistent Address: http://dx.doi.org/10.53846/goediss-8679

 

 

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Abstract

English

Although cancer is among the most common causes of death worldwide, successful treatment options for most cancer entities remain elusive, raising the need for novel therapies. One attractive target of current drug candidates is the stress-inducible heat shock protein 90 (HSP90) chaperone machinery. Its normal chaperoning function is subverted in tumors to protect numerous mutated and overexpressed proteins from misfolding and degradation. Hence, it is playing a central role in oncogenic signaling. The addiction of cancer cells to the HSP90 chaperone machinery provides opportunities for targeting the stability of HSP90-dependent oncoproteins (clients). To dissect the importance of the HSP90 chaperone machinery in tumor progression, we investigated two HSP90-stabilized proteins: the macrophage migration inhibitory factor (MIF) in colorectal cancer (CRC) and mutant p53 (mutp53) in pancreatic ductal adenocarcinoma (PDAC). Both proteins were shown to be elevated in cancer cells via the HSP90 chaperone machinery, correlating with worse prognosis for cancer patients. MIF is a pro-inflammatory cytokine which is known to promote tumor progression in various cancer entities. Indeed, we demonstrate that loss of HSP90-stabilized MIF in CRC results in reduced tumor growth. This effect was accompanied by decreased macrophage recruitment and angiogenesis in established CRC tumors. Our data suggest that MIF acts via the CD74/MAPK axis and is indeed a cancer-relevant HSP90 client in CRC. The tumor suppressor p53 (p53) is mutated in approximately 50% of all human cancers. We found that the mutp53R248W variant is highly stabilized by the HSP90 chaperone machinery in pancreatic ductal adenocarcinoma (PDAC) cells. Furthermore, we identified a unique gain-of-function role of this p53R248W mutant on cell migration. Mechanistically, mutp53R248W specifically interacts with the phosphorylated transcription factor STAT3 and thus contributes to the aggressiveness of pancreatic cancer. Our results further corroborate HSP90 as an attractive target to counteract tumor development, and we identified two HSP90 clients as cancer drivers, outlining additional target structures for cancer therapy.
Keywords: Macrophage migration inhibitory factor; Mutant p53; Heat shock protein 90; Colorectal cancer; Pancreatic ductal adenocarcinoma
 
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