Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, I‑71122 Foggia, Italy.
Laboratory of Pre‑Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, I-85028 Rionero in Vulture, Potenza, Italy.
Int J Oncol. 2022 Jun;60(6). doi: 10.3892/ijo.2022.5369. Epub 2022 May 11.
Metabolic rewiring fuels rapid cancer cell proliferation by promoting adjustments in energetic resources, and increasing glucose uptake and its conversion into lactate, even in the presence of oxygen. Furthermore, solid tumors often contain hypoxic areas and can rapidly adapt to low oxygen conditions by activating hypoxia inducible factor (HIF)‑1α and several downstream pathways, thus sustaining cell survival and metabolic reprogramming. Since TNF receptor‑associated protein 1 (TRAP1) is a HSP90 molecular chaperone upregulated in several human malignancies and is involved in cancer cell adaptation to unfavorable environments and metabolic reprogramming, in the present study, its role was investigated in the adaptive response to hypoxia in human colorectal cancer (CRC) cells and organoids. In the present study, glucose uptake, lactate production and the expression of key metabolic genes were evaluated in TRAP1‑silenced CRC cell models under conditions of hypoxia/normoxia. Whole genome gene expression profiling was performed in TRAP1‑silenced HCT116 cells exposed to hypoxia to establish the role of TRAP1 in adaptive responses to oxygen deprivation. The results revealed that TRAP1 was involved in regulating hypoxia‑induced HIF‑1α stabilization and glycolytic metabolism and that glucose transporter 1 expression, glucose uptake and lactate production were partially impaired in TRAP1‑silenced CRC cells under hypoxic conditions. At the transcriptional level, the gene expression reprogramming of cancer cells driven by HIF‑1α was partially inhibited in TRAP1‑silenced CRC cells and organoids exposed to hypoxia. Moreover, Gene Set Enrichment Analysis of TRAP1‑silenced HCT116 cells exposed to hypoxia demonstrated that TRAP1 was involved in the regulation of ribosome biogenesis and this occurred with the inhibition of the mTOR pathway. Therefore, as demonstrated herein, TRAP1 is a key factor in maintaining HIF‑1α‑induced genetic/metabolic program under hypoxic conditions and may represent a promising target for novel metabolic therapies.
代谢重编程通过促进能量资源的调整以及增加葡萄糖摄取及其转化为乳酸来促进癌细胞的快速增殖，即使在有氧气的情况下也是如此。此外，实体瘤通常包含缺氧区域，并且可以通过激活缺氧诱导因子 (HIF)-1α 和几种下游途径来快速适应低氧条件，从而维持细胞存活和代谢重编程。由于 TNF 受体相关蛋白 1 (TRAP1) 是几种人类恶性肿瘤中上调的 HSP90 分子伴侣，并且参与癌细胞适应不利环境和代谢重编程，因此在本研究中，研究了其在人结直肠癌 (CRC) 细胞和类器官对缺氧适应中的作用。在本研究中，在缺氧/常氧条件下，在沉默 TRAP1 的 CRC 细胞模型中评估了葡萄糖摄取、乳酸生成和关键代谢基因的表达。在暴露于缺氧的沉默 TRAP1 的 HCT116 细胞中进行全基因组基因表达谱分析，以确定 TRAP1 在适应缺氧的反应中的作用。结果表明，TRAP1 参与调节缺氧诱导的 HIF-1α 稳定和糖酵解代谢，并且在缺氧条件下沉默 TRAP1 的 CRC 细胞中葡萄糖转运蛋白 1 表达、葡萄糖摄取和乳酸生成部分受损。在转录水平上，在暴露于缺氧的沉默 TRAP1 的 CRC 细胞和类器官中，部分抑制了由 HIF-1α 驱动的癌细胞基因表达重编程。此外，对暴露于缺氧的沉默 TRAP1 的 HCT116 细胞进行基因集富集分析表明，TRAP1 参与核糖体生物发生的调节，并且这伴随着 mTOR 途径的抑制。因此，如本文所示，TRAP1 是在缺氧条件下维持 HIF-1α 诱导的遗传/代谢程序的关键因素，并且可能成为新型代谢治疗的有前途的靶标。
