Gonzalez Gil A, Osuji Ezinne U, Fiur Natalie C, Clark Matthew G, Ma Seohee, Lukov Laura L, Zhang Chi
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
Chem Biomed Imaging. 2024 Oct 21;3(1):25-34. doi: 10.1021/cbmi.4c00050. eCollection 2025 Jan 27.
Due to uncontrolled cell proliferation and disrupted vascularization, many cancer cells in solid tumors have limited oxygen supply. The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells, contributing to therapy resistance and metastasis. To identify better targets for the effective removal of hypoxia-adaptive cancer cells, it is crucial to understand how cancer cells alter their metabolism in hypoxic conditions. Here, we studied lipid metabolic changes in cancer cells under hypoxia using coherent Raman scattering (CRS) microscopy. We discovered the accumulation of lipid droplets (LDs) in the endoplasmic reticulum (ER) in hypoxia. Time-lapse CRS microscopy revealed the release of old LDs and the reaccumulated LDs in the ER during hypoxia exposure. Additionally, we explored the impact of carbon sources on LD formation and found that MIA PaCa2 cells preferred fatty acid uptake for LD formation, while glucose was essential to alleviate lipotoxicity. Hyperspectral-stimulated Raman scattering (SRS) microscopy revealed a reduction in cholesteryl ester content and a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2 cancer cells. This alteration in LD content is linked to reduced efficacy of treatments targeting cholesteryl ester formation. This study unveils important lipid metabolic changes in hypoxic cancer cells, providing insights that could lead to better treatment strategies for hypoxia-resistant cancer cells.
由于细胞增殖失控和血管生成紊乱，实体瘤中的许多癌细胞氧气供应有限。肿瘤的低氧微环境导致癌细胞代谢重编程，从而产生治疗抗性和转移。为了确定更好的靶点以有效清除适应低氧的癌细胞，了解癌细胞在低氧条件下如何改变其代谢至关重要。在此，我们使用相干拉曼散射（CRS）显微镜研究了低氧条件下癌细胞的脂质代谢变化。我们发现低氧时内质网（ER）中脂滴（LDs）的积累。延时CRS显微镜显示在低氧暴露期间，旧脂滴从内质网中释放以及新脂滴在内质网中重新积累。此外，我们探讨了碳源对脂滴形成的影响，发现MIA PaCa2细胞在形成脂滴时更倾向于摄取脂肪酸，而葡萄糖对于减轻脂毒性至关重要。高光谱受激拉曼散射（SRS）显微镜显示低氧的MIA PaCa2癌细胞中胆固醇酯含量降低以及脂滴的脂质饱和度水平下降。脂滴含量的这种改变与靶向胆固醇酯形成的治疗效果降低有关。本研究揭示了低氧癌细胞中重要的脂质代谢变化，为针对抗低氧癌细胞的更好治疗策略提供了见解。
