Good news! Cancer is history (soon)!
"Cancer cells have a voracious appetite, rapidly consuming nutrients to sustain unchecked growth. Many cancers carrying mutations in the tumor-suppressor gene TP53 are particularly dependent on cholesterol production, using the lipid as a key fuel source for proliferation. ..."
"Scientists have found a potential new way to tackle aggressive cancers by altering how tumour cells process cholesterol in mice.
The team created a ‘cholesterol traffic jam’ in cancer cells with a mutation in the tumour-suppressing gene TP53 by disrupting the enzymes that move the lipid around a cell — phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks). “When you delete these kinases, the animals are 100 percent protected and never develop a tumour,” ... Targeting PI5P4Ks could be a new treatment strategy for tumours that often have TP53 mutations, such as breast cancers."
"... The scientists conducted experiments in mouse and human cancer cells showing that PI5P4Ks influenced the movement and behavior of organelles that carry cholesterol around our cells. In cancer cells with TP53 mutations and PI5P4Ks, cholesterol-laden lysosomes were found near the exterior cell membrane. Without PI5P4Ks, lysosomes remained in the interior of the cells, near the nucleus. ...
location is critical for lysosomes transporting cholesterol. While positioned near the edge of the cell, lysosomes and their cargo are in proximity with many receptor proteins, enzymes and signaling molecules that exist around the cell membrane. This includes mechanistic target of rapamycin complex 1 (mTORC1), an enzyme that governs cell growth and runs amok in cancer. ..."
From the abstract:
"In p53-deficient cancers, targeting cholesterol metabolism has emerged as a promising therapeutic approach, given that p53 loss dysregulates sterol regulatory element-binding protein 2 pathways, thereby enhancing cholesterol biosynthesis. While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquired resistance. Consequently, strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport.
In this study, we investigate a previously underexplored function of PI5P4Ks, which catalyzes the conversion of PI(5)P to PI(4,5)P2 at intracellular membranes. Our findings reveal that PI5P4Ks play a key role in facilitating lysosomal cholesterol transport, regulating lysosome positioning, and sustaining growth signaling via the mechanistic target of rapamycin (mTOR) pathway. While PI5P4Ks have previously been implicated in mTOR signaling and tumor proliferation in p53-deficient contexts, this work elucidates an upstream mechanism that unifies these earlier observations."
The Loss of Cholesterol Transport Enzymes Impedes Tumor Growth "Kinases that shuttle cholesterol within tumor cells help fuel growth. Blocking these enzymes may starve cancer cells, suggesting a promising therapeutic target."
Cholesterol-craving cancers need lipid enzymes to use metabolites for growth (original news release) "Study finds kinases move cholesterol in the cell to where it can activate a growth pathway in many aggressive cancers"
Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking (open access)
Fig. 1. PI5P4Ks are crucial for support of tumor maintenance and are rarely mutated in human cancer.
Fig. 4. Breast cancer cells require PI5P4Ks for survival and cholesterol sensing.
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