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Aldehyde Dehydrogenase 2 (ALDH2): A novel sorafenib target in hepatocellular carcinoma unraveled by the proteome-wide cellular thermal shift assay. | LitMetric

AI Article Synopsis

  • Sorafenib is a drug used as the first-line treatment for liver cancer that cannot be surgically removed, but its exact mechanisms of action are not fully understood.
  • Researchers used a technique called Cellular Thermal Shift Assay combined with Mass Spectrometry to identify proteins that sorafenib binds to, discovering that it interacts with the enzyme aldehyde dehydrogenase 2 (ALDH2), important for breaking down alcohol.
  • The study shows that sorafenib inhibits ALDH2's activity and that levels of ALDH2 are lower in cells resistant to sorafenib, suggesting that ALDH2 may play a role in how effective sorafenib is against liver cancer.*

Article Abstract

Sorafenib is a multikinase inhibitor indicated for first-line treatment of unresectable hepatocellular carcinoma. Despite its widespread use in the clinic, the existing knowledge of sorafenib mode-of-action remains incomplete. To build upon the current understanding, we used the Cellular Thermal Shift Assay (CETSA) coupled to Mass Spectrometry (CETSA-MS) to monitor compound binding to its target proteins in the cellular context on a proteome-wide scale. Among the potential sorafenib targets, we identified aldehyde dehydrogenase 2 (ALDH2), an enzyme that plays a major role in alcohol metabolism. We validated the interaction of sorafenib with ALDH2 by orthogonal methods using pure recombinant protein, proving that this interaction is not mediated by other cellular components. Moreover, we showed that sorafenib inhibits ALDH2 activity, supporting a functional role for this interaction. Finally, we were able to demonstrate that both ALDH2 protein expression and activity were reduced in sorafenib-resistant cells compared to the parental cell line. Overall, our study allowed the identification of ALDH2 as a novel sorafenib target and sheds light on its potential role in both hepatocellular carcinoma and sorafenib resistance condition.

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Source
http://dx.doi.org/10.1016/j.slasd.2024.100154DOI Listing

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