通过阻断丙酮酸流入线粒体来增强糖酵解能力可使前列腺癌对检测和放射治疗更敏感。
Glycolytic potential enhanced by blockade of pyruvate influx into mitochondria sensitizes prostate cancer to detection and radiotherapy.
机构信息
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Department of Urology, Shanghai Ninth People's Hospital, Shanghai 200011, China.
出版信息
Cancer Biol Med. 2022 Aug 17;19(9):1315-33. doi: 10.20892/j.issn.2095-3941.2021.0638.
OBJECTIVE
This study aimed to evaluate the effects of mitochondrial pyruvate carrier (MPC) blockade on the sensitivity of detection and radiotherapy of prostate cancer (PCa).
METHODS
We investigated glycolysis reprogramming and MPC changes in patients with PCa by using metabolic profiling, RNA-Seq, and tissue microarrays. Transient blockade of pyruvate influx into mitochondria was observed in cellular studies to detect its different effects on prostate carcinoma cells and benign prostate cells. Xenograft mouse models were injected with an MPC inhibitor to evaluate the sensitivity of F-fluorodeoxyglucose positron emission tomography with computed tomography and radiotherapy of PCa. Furthermore, the molecular mechanism of this different effect of transient blockage towards benign prostate cells and prostate cancer cells was studied .
RESULTS
MPC was elevated in PCa tissue compared with benign prostate tissue, but decreased during cancer progression. The transient blockade increased PCa cell proliferation while decreasing benign prostate cell proliferation, thus increasing the sensitivity of PCa cells to F-PET/CT (SUVavg, = 0.016; SUVmax, = 0.03) and radiotherapy ( < 0.01). This differential effect of MPC on PCa and benign prostate cells was dependent on regulation by a VDAC1-MPC-mitochondrial homeostasis-glycolysis pathway.
CONCLUSIONS
Blockade of pyruvate influx into mitochondria increased glycolysis levels in PCa but not in non-carcinoma prostate tissue. This transient blockage sensitized PCa to both detection and radiotherapy, thus indicating that glycolytic potential is a novel mechanism underlying PCa progression. The change in the mitochondrial pyruvate influx caused by transient MPC blockade provides a critical target for PCa diagnosis and treatment.
目的
本研究旨在评估线粒体丙酮酸载体（MPC）阻断对前列腺癌（PCa）检测和放疗敏感性的影响。
方法
我们通过代谢组学、RNA-Seq 和组织微阵列研究了 PCa 患者的糖酵解重编程和 MPC 变化。在细胞研究中观察到短暂阻断丙酮酸流入线粒体，以检测其对前列腺癌细胞和良性前列腺细胞的不同影响。在异种移植小鼠模型中注射 MPC 抑制剂，以评估 F-氟脱氧葡萄糖正电子发射断层扫描与计算机断层扫描和 PCa 放疗的敏感性。此外，还研究了这种短暂阻断对良性前列腺细胞和前列腺癌细胞的不同作用的分子机制。
结果
与良性前列腺组织相比，PCa 组织中的 MPC 升高，但在癌症进展过程中降低。短暂阻断增加了 PCa 细胞的增殖，同时减少了良性前列腺细胞的增殖，从而提高了 PCa 细胞对 F-PET/CT（SUVavg， = 0.016；SUVmax， = 0.03）和放疗（ < 0.01）的敏感性。MPC 对 PCa 和良性前列腺细胞的这种差异作用取决于 VDAC1-MPC-线粒体稳态-糖酵解途径的调节。
结论
阻断丙酮酸流入线粒体增加了 PCa 中的糖酵解水平，但对非癌前列腺组织没有影响。这种短暂阻断使 PCa 对检测和放疗都更加敏感，这表明糖酵解潜力是 PCa 进展的一个新机制。MPC 短暂阻断引起的线粒体丙酮酸流入的变化为 PCa 的诊断和治疗提供了一个关键靶点。
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