Charlestin Verodia, Tan Elijah, Arias-Matus Carlos Eduardo, Wu Junmin, Miranda-Vergara Maria Cristina, Lee Mijoon, Wang Man, Nannapaneni Dharma T, Tennakoon Parinda, Blagg Brian S J, Ashfeld Brandon L, Kaliney William, Li Jun, Littlepage Laurie E
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Harper Cancer Research Institute, South Bend, IN 46617, USA.
Cancers (Basel). 2024 Jul 30;16(15):2714. doi: 10.3390/cancers16152714.
AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance.
水通道蛋白（AQPs）促进乳腺癌的进展和转移。我们之前发现，对Aqp7进行基因抑制可减轻乳腺癌的原发性肿瘤负担并减少转移。在本研究中，我们使用了两种AQP抑制剂Auphen和Z433927330，来评估治疗性抑制AQPs在乳腺癌治疗中的疗效。在小鼠和人乳腺癌细胞系中，对这两种抑制剂进行了细胞毒性和代谢稳定性分析，以评估其在乳腺癌中的作用。两种AQP抑制剂还影响了其他AQP转录本和蛋白质的表达，这表明AQP家族成员之间存在代偿性调节。作为单一药物，Auphen体内治疗可延长总生存期，但不影响原发性或转移性肿瘤负担。然而，Auphen治疗使细胞对化疗（阿霉素）或内分泌治疗（他莫昔芬、氟维司群）更敏感。事实上，他莫昔芬治疗可降低AQP7蛋白的总体表达。对用Auphen处理的乳腺癌细胞进行RNA测序，确定线粒体代谢基因受Auphen影响，这可能有助于减少乳腺肿瘤进展、肺转移，并提高乳腺癌内分泌治疗的疗效。有趣的是，我们发现Auphen和他莫昔芬协同作用可降低乳腺癌细胞活力，这表明Auphen治疗使细胞对他莫昔芬更敏感。总之，本研究强调AQPs是乳腺癌转移的治疗靶点，具有前景且值得开发利用。然而，药理学结果表明，需要对AQP抑制进行进一步的化学改进和优化，以使这些AQP抑制剂适用于克服内分泌治疗耐药性的治疗获益。
