Fatty Acid Binding Protein 5 Regulates Docetaxel Sensitivity in Taxane-Resistant Prostate Cancer Cells

Prostate cancer is a leading cause of cancer-related deaths in men in the United States. Although treatable when detected early, prostate cancer commonly transitions to an aggressive castration-resistant metastatic state. While taxane chemotherapeutics such as docetaxel are mainstay treatment options for prostate cancer, taxane resistance often develops. Fatty acid binding protein 5 (FABP5) is an intracellular lipid chaperone that is upregulated in advanced prostate cancer and is implicated as a key driver of its progression. The recent demonstration that FABP5 inhibitors produce synergistic inhibition of tumor growth when combined with taxane chemotherapeutics highlights the possibility that FABP5 may regulate other features of taxane function, including resistance. Employing taxane-resistant DU145-TXR cells and a combination of cytotoxicity, apoptosis, and cell cycle assays, our findings demonstrate that FABP5 knockdown sensitizes the cells to docetaxel. In contrast, docetaxel potency was unaffected by FABP5 knockdown in taxane-sensitive DU145 cells. Taxane-resistance in DU145-TXR cells stems from upregulation of the P-glycoprotein ATP binding cassette subfamily B member 1 (ABCB1). Expression analyses and functional assays confirmed that FABP5 knockdown in DU145-TXR cells markedly reduced ABCB1 expression and activity, respectively. Our study demonstrates a potential new function for FABP5 in regulating taxane sensitivity and the expression of a major P-glycoprotein efflux pump in prostate cancer cells.

前列腺癌是美国男性癌症相关死亡的首要病因。尽管早期检出可获得治愈，但前列腺癌通常会进展为侵袭性去势抵抗性转移状态。紫杉烷类化疗药物（如多西他赛）是前列腺癌的主流治疗选择，但肿瘤常对紫杉烷产生耐药性。脂肪酸结合蛋白5（Fatty acid binding protein 5, FABP5）是一种细胞内脂质伴侣，在晚期前列腺癌中表达上调，且被证实是前列腺癌进展的关键驱动因子。近期研究表明，FABP5抑制剂与紫杉烷类化疗药物联用时可协同抑制肿瘤生长，这提示FABP5可能调控紫杉烷功能的其他特征，包括耐药性。本研究使用耐紫杉烷的DU145-TXR细胞，并结合细胞毒性、细胞凋亡及细胞周期实验，结果显示FABP5敲低可使细胞对多西他赛敏感。与之相反，在紫杉烷敏感的DU145细胞中，FABP5敲低不会影响多西他赛的药效。DU145-TXR细胞的紫杉烷耐药性源于P-糖蛋白ATP结合盒亚家族B成员1（ATP binding cassette subfamily B member 1, ABCB1）的表达上调。表达分析与功能实验证实，在DU145-TXR细胞中敲低FABP5可分别显著降低ABCB1的表达与活性。本研究揭示了FABP5在调控前列腺癌细胞对紫杉烷的敏感性及主要P-糖蛋白外排泵表达方面的潜在新功能。