AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol.
AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol.
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DOI：
10.1158/2767-9764.crc-23-0235
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发表时间：
2023-09-19
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雄激素受体信号传导抑制剂（ARSI）用于治疗去势抵抗性前列腺癌（CRPC），以阻止雄激素受体（AR）信号传导的复苏。尽管早期取得了成功，但ARSI患者最终会复发，产生耐药性，并死于疾病。耐药可能通过醛酮还原酶家族1C成员3（AKR1C3）上调介导的瘤内类固醇生成而发生。接受亮丙瑞林（去势）治疗的患者和接受亮丙瑞林+阿比特龙（阿比特龙治疗后）治疗的患者体内存在DHEA-S，可通过AKR1C3促进睾酮（T）生物合成，导致前列腺癌细胞生长复苏。我们证明了在去势和阿比特龙后患者中发现的DHEA-S浓度（i）在前列腺癌细胞中以AKR1C3依赖的方式转化为T，以及（ii）足以刺激AKR1C3依赖的细胞生长的量。我们分别在原发性和转移性前列腺癌细胞系CWR22PC和DuCaP中观察到这一点。雄激素测量通过稳定同位素稀释LC-MS/MS进行。我们使用稳定的短发夹RNA敲低和药理学抑制剂证明AKR1C3依赖性。我们还证明，游离DHEA被AKR1C3还原为5-雄甾烯-3 β，17 β-二醇（5-Adiol），这是一种主要代谢产物，表明在我们的细胞系中，5-Adiol是T的主要前体。我们已经确定了一种对原发性和转移性细胞系共同的ARSI抗性机制，该机制依赖于AKR1C3催化的DHEA向T途径上的5-Adiol的转化。我们发现，ARSI治疗后保留的DHEA-S库在原发性和转移性前列腺癌细胞中转化为T，其量足以刺激细胞生长。药理学和遗传学方法表明，AKR1C3是这些作用所必需的。此外，到T的途径通过5-Adiol进行。我们认为这是ARSI耐药的一种机制。
Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) to stop a resurgence of androgen receptor (AR) signaling. Despite early success, patients on ARSIs eventually relapse, develop drug resistance, and succumb to the disease. Resistance may occur through intratumoral steroidogenesis mediated by upregulation of aldo-keto reductase family 1C member 3 (AKR1C3). Patients treated with leuprolide (castrate) and those treated with leuprolide plus abiraterone (post-Abi) harbor a reservoir of DHEA-S which could fuel testosterone (T) biosynthesis via AKR1C3 to cause a resurgence of prostate cancer cell growth. We demonstrate that concentrations of DHEA-S found in castrate and post-Abi patients are (i) converted to T in an AKR1C3-dependent manner in prostate cancer cells, and (ii) in amounts sufficient to stimulate AKR1C3-dependent cell growth. We observed this in primary and metastatic prostate cancer cell lines, CWR22PC and DuCaP, respectively. Androgen measurements were made by stable isotope dilution LC-MS/MS. We demonstrate AKR1C3 dependence using stable short hairpin RNA knockdown and pharmacologic inhibitors. We also demonstrate that free DHEA is reduced to 5-androstene-3β,17β-diol (5-Adiol) by AKR1C3 and that this is a major metabolite, suggesting that in our cell lines 5-Adiol is a predominant precursor of T. We have identified a mechanism of ARSI resistance common to both primary and metastatic cell lines that is dependent on the conversion of DHEA to 5-Adiol on route to T catalyzed by AKR1C3. We show that reservoirs of DHEA-S that remain after ARSI treatment are converted into T in primary and metastatic prostate cancer cells in amounts sufficient to stimulate cell growth. Pharmacologic and genetic approaches demonstrate that AKR1C3 is required for these effects. Furthermore, the route to T proceeds through 5-Adiol. We propose that this is a mechanism of ARSI drug resistance.
影响因子：
5.1
作者：
Tamae, Daniel;Mostaghel, Elahe;Montgomery, Bruce;Nelson, Peter S.;Balk, Steven P.;Kantoff, Philip W.;Taplin, Mary-Ellen;Penning, Trevor M.
通讯作者：
Penning, Trevor M.