Abstract 2372: Targeting a metabolic compensatory mechanism for heat shock factor 1 inhibition in prostate cancer
Authors: Hauck J. Spencer , Gao Xia , Butler William , Xu Lingfan , Huang Jiaoti 
Published: June 2022

While inhibition of androgen receptor signaling has greatly improved the outcome for many prostate cancer patients (PCa), there are limited therapeutic interventions for advanced and metastatic PCa. Heat shock factor 1 (HSF1) is activated by cellular stress and regulates transcription, proteome stability, and oxidative stress. HSF1 is elevated in aggressive cancers from many tissue types and has been directly implicated in driving cancer progression. We found that HSF1 predicts survival for metastatic castration resistant prostate cancer patients, who are unable to be treated by inhibition of the androgen receptor signaling. In comparison to benign prostate tissue, HSF1 had increased protein levels in primary PCa, castration resistant PCa, and small cell neuroendocrine carcinoma the most aggressive histologic type of PCa. Knockdown of HSF1 decreases cellular growth in PCa cell lines. In collaboration with the laboratory of Dr. Dennis Thiele, we identified a direct HSF inhibitor that targets nuclear HSF1 for degradation. Prostate cancer cells experience cellular senescence when treated with the HSF1 inhibitor. To better understand how HSF1 regulates PCa cellular growth, we investigated metabolic changes in response to the selective HSF1 inhibitor. We found that a rate limiting enzyme in the transsulfuration pathway was reproducibly altered after HSF1 knockdown and pharmacological inhibition. This is the first linkage of HSF1 and the transsulfuration pathway in cancer. The transsulfuration pathway is important for production of cellular energy in the form of pyruvate, so overactive HSF1 likely increases cellular growth through increased pyruvate production. The transsulfuration pathways also produces the antioxidant hydrogen sulfide. The increased production of antioxidants likely aid cancer cells in responding to the accumulation of reactive oxygen species that form in cancer cells from oncogene activation, decreased blood supply, and tumor hypoxia. We have identified novel HSF1 binding sites in the gene encoding this transsulfuration pathway enzyme, which regulate levels of gene expression. Small cell neuroendocrine carcinoma cells treated with both the selective HSF1 inhibitor and the transsulfuration pathway inhibitor have reduced growth and increased cellular death by caspase 3 cleavage. Targeting the transsulfuration pathway in combination with HSF1 inhibition may delay recurrence in PCa patients by killing tumor cells instead of solely inducing cellular senescence. Since HSF1 is increased in many forms of cancer, these data may provide novel therapeutic targets for aggressive cancer from many tissue types.

Citation Format: J. Spencer Hauck, Xia Gao, William Butler, Lingfan Xu, Jiaoti Huang. Targeting a metabolic compensatory mechanism for heat shock factor 1 inhibition in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2372.