Statins effectively kill metastasis-driving cancer cells that are HIF-1α dominant, suggesting HIF-1α rather than cholesterol-lowering action mediates statin sensitivity in aggressive cancers.
Do statins exert cytotoxicity against aggressive metastatic cancers via HIF-1α rather than the cholesterol pathway?
Statins may kill aggressive metastatic cancers through a HIF-1α-mediated mechanism rather than their traditional cholesterol-lowering pathway.
Abstract Statins are a class of small molecule, FDA approved drugs that are widely used to combat cardiovascular disease due to their cholesterol lowering effects. Traditionally, they are competitive inhibitors of HMG-CoA Reductase (HMGCR), a critical enzyme involved in cholesterol synthesis. Previous studies in our lab highlighted that various kinds of statins can effectively kill metastasis-driving clear cell renal cell carcinoma (ccRCC) cells that are von Hippel-Lindau gene (VHL) negative, hypoxia inducible factor (HIF)-1α dominant, while sparing the less aggressive VHL positive, HIF-2α dominant cells. Similar to this metastasis driving ccRCC subpopulation, other aggressive cancers such as triple negative breast cancer (TNBC), and neuroendocrine prostate cancer (NEPC) share the same features of HIF-1α dominance and statin sensitivity. While statins’ cytotoxicity for cancer is well documented, there is still no consensus on their mechanism of action nor is there a rationale explaining why statins are better at killing aggressive cancers. Our findings suggest that HIF-1α could be the target in statin metastasis-blocking mechanism, rather than its known cholesterol-lowering action. This project uses a multi-pronged approach involving qRT-PCR, western blot, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockouts to rule out the role of HMGCR and the cholesterol pathway in statin cytotoxicity in all three cancer models (ccRCC, TNBC, and NEPC). By understanding the possible role that the HIF-1α proteins play in mediating statin sensitivity, we aim to further clarify their mechanism of action in aggressive metastatic cancers and make a step forward in developing a new safe and effective drug that can both prevent and treat these cancers. Citation Format: Jimin Kim, Shannon Shams, Diana Vaca, Junhui Hu, Moe Ishihara, Khiara Threets, Robert Damoiseaux, Lily Wu. Assessing statin sensitivity and hypoxia regulation in aggressive metastatic cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3162.
Kim et al. (Fri,) conducted a other in Aggressive metastatic cancers (ccRCC, TNBC, NEPC). Statins was evaluated on Role of HMGCR and cholesterol pathway in statin cytotoxicity. Statins effectively kill metastasis-driving cancer cells that are HIF-1α dominant, suggesting HIF-1α rather than cholesterol-lowering action mediates statin sensitivity in aggressive cancers.