Abstract
This study aims to explore lipidic mechanism towards low‐density lipoprotein receptor (LDLR)‐mediated platinum chemotherapy resistance. By using the lipid profiling technology, LDLR knockdown was found to increase lysosomal lipids and decrease membranous lipid levels in EOC cells. LDLR knockdown also down‐regulated ether‐linked phosphatidylethanolamine (PE‐O, lysosomes or peroxisomes) and up‐regulated lysophosphatidylcholine [LPC, lipid droplet (LD)]. This implies that the manner of using Lands cycle (conversion of lysophospholipids) for LDs might affect cisplatin sensitivity. The bioinformatics analyses illustrated that LDLR‐related lipid entry into LD, rather than an endogenous lipid resource (eg Kennedy pathway), controls the EOC prognosis of platinum chemotherapy patients. Moreover, LDLR knockdown increased the number of platinum‐DNA adducts and reduced the LD platinum amount. By using a manufactured LPC‐liposome‐cisplatin (LLC) drug, the number of platinum‐DNA adducts increased significantly in LLC‐treated insensitive cells. Moreover, the cisplatin content in LDs increased upon LLC treatment. Furthermore, lipid profiles of 22 carcinoma cells with differential cisplatin sensitivity (9 sensitive vs 13 insensitive) were acquired. These profiles revealed low storage lipid levels in insensitive cells. This result recommends that LD lipidome might be a common pathway in multiple cancers for platinum sensitivity in EOC. Finally, LLC suppressed both cisplatin‐insensitive human carcinoma cell training and testing sets. Thus, LDLR‐platinum insensitivity can be due to a defective Lands cycle that hinders LPC production in LDs. Using lipidome assessment with the newly formulated LLC can be a promising cancer chemotherapy method.
Highlights
Platinum-based chemotherapy is the primary modality used for treating patients with solid tumours
Among the various reported mechanisms, the most acceptable hypothesis in this field was the expression of ATP-binding cassette (ABC) gene family in cancer cells.[4,5]
We found that high low-density lipoprotein receptor (LDLR) uptake genes were associated with a poor progression-free survival (PFS) (Figure 2A,C)
Summary
Platinum-based chemotherapy is the primary modality used for treating patients with solid tumours. The expression of the ABC gene family can pump the intracellular chemotherapy drug out of the cells to avoid the cytotoxic effect.[6]. The use of an ABC gene blocker was tested for treating multiple drug resistance; the results were controversial. No evidence suggests ABC blockers to be an effective second-line chemotherapy drug. LDLR expression reprogrammes cellular transcriptome associated with lipid metabolism (Lands cycle in LD) to be the mechanism underlying cisplatin sensitivity. Abundant evidence has indicated that intracellular lipid resources, either endogenous or exogenous, are the key biochemical event indicating chemotherapy responsiveness of multiple cancers. We explored LDLR-mediated lipidome alteration for platinum therapy sensitivity by using lipidomics and bioinformatics approaches for illustrating cellular lipidome and testing the hypothesis that targeting lipidome, instead of gene expressions, is a useful therapeutic strategy
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