PRostate cancer, a major health concern for men in the United States, is often associated with an imbalance between antioxidants and prooxidants, exacerbating the situation into harmful oxidative stress. Masu. This association has sparked interest in whether dietary antioxidants can reduce oxidative stress and potentially reduce prostate cancer risk. Twenty years ago, the National Cancer Institute began a large study of more than 35,000 men to find out whether selenium and vitamin E could help prevent prostate cancer. However, the results showed that There is little benefit to either antioxidant supplemented and clarified Increased risk of prostate cancer Contains vitamin E.1, 2
Lloyd Trotman explores the space between discovery and basic research to develop cancer models for functional analysis of how cancer develops and how clinicians treat it. I am.
Cold Spring Harbor Laboratory
These discoveries left a deep impression Lloyd TrotmanHe was a molecular biologist at Cold Spring Harbor Laboratory and was a keen observer of ongoing clinical trials. Although the results did not meet the researchers’ expectations, Trotman said, “Unexpected results that go against what you think is most reliable are because you turned a blind eye.” said. Subsequent work by other groups showed that antioxidant-responsive genes act as oncogenes rather than tumor suppressors, prompting Trotman to explore an interesting alternative. So, could pro-oxidants be a viable alternative to slowing the progression of prostate cancer?
Trotman focused on the prooxidant menadione sodium bisulfate (MSB), a precursor to vitamin K commonly found in leafy vegetables. Recently, there is paper Published in scienceTrotman and his team discovered that MSB promotes prostate cancer cell death by targeting key lipid kinases in the endosomal pathway.3 This disrupts cell sorting and causes oxidative cell death. The research team also linked this kinase to a serious muscle disease, X-linked myotubular myopathy, highlighting the broad potential of this approach for potential therapeutic effects of pro-oxidants.
To test the effectiveness of MSB treatment, Trotman prostate cancer mouse model Something his team had previously developed.4 They gave the mice one of three drinking treatments: water, water-soluble MSB, or a combination of water-soluble MSB and vitamin C. Despite its reputation as a classic antioxidant, vitamin C exerts its effects. oxidation effect against cancer cells.5
Trotman hoped for a synergistic effect between MSB and vitamin C. However, when the researchers measured the abundance of MSB in the mouse prostates, only MSB was firmly present. This therapy not only effectively delivered MSB to the prostate, but MSB more effectively suppressed prostate tumor progression. Subsequent analysis revealed that increased oxidative stress caused MSB-induced slowing.
Using the same mouse model, Trotman’s team tested the standard-of-care surgical castration treatment. However, castration alone was not enough to stop the cancer’s attack. Initial treatment responses quickly developed resistance and progression of fatal disease. Cancer cells eventually mutate to resist treatment, so understanding this process can give researchers clues about how these cancer cells protect themselves. Masu.
Trotman used mononuclear whole genome sequencing across 100 cancer cell lines to identify potential mechanisms behind MSB-induced disease regression and resistance. The researchers treated each cell line with increasing concentrations of MSB for 24 hours and then measured cell viability. They found that under the oxidative pressure of MSB, resistant cells strengthened their antioxidant defenses. “So we can assume that this therapy had the effect we hoped it would have,” Trotman explained.
To better understand how MSB inhibits disease progression, researchers sought to identify the targets of this oxidative stress. First, Trotman and his team investigated whether MSB triggers mitochondrial or lysosomal cell death pathways. Surprisingly, MSB didn’t trigger either. “this [cellular] The killing occurred through mechanisms that are neither explained nor fit within existing paradigms. ”
To characterize this pathway, the researchers used a CRISPR-Cas9 screen on two metastatic prostate cancer cell lines to identify key genes. One of the outstanding genes is encodes vacuolar protein sorting 34 (VPS34), which produces signaling lipids that play a role in transporting proteins and lipids within cells. In endosomes, this lipid, called phosphatidylinositol 3-phosphate (PI(3)P), acts like a molecular ID tag that guides cargo to the cell membrane or marks it for lysosomal degradation.
Through human and mouse cell line experiments, the researchers found that MSB oxidizes cysteine required for VPS34 function, which depletes PI(3)P levels on endosomal membranes. Without this molecular ID tag, cells are unable to sort cellular material, and untagged endosomes accumulate and eventually rupture. These findings reveal a distinct pathway by which MSB kills prostate cancer cells through lipid depletion. Researchers named this redox-sensitive cell death process triaptosis.
“There’s a lot we need to know about vitamin K and how it works, because a recently recognized function of vitamin K is that it acts as an antioxidant. ” he said. joellen welsha nutritional biochemist at the University at Albany. Although the study results showing pro-oxidant effects surprised her, “no one has really studied the different forms of vitamin K, so it’s nice to see the group focus on menadione.” she said.
Intrigued by the role of VPS34 in prostate cancer, Trotman wondered if MSB could address another disease associated with this protein: X-linked myotubular myopathy (XLMTM). This devastating disease, which inhibits muscle growth, often kills boys before they reach adulthood. XLMTM is derived from mutated myotubularin 1 (MTM1) gene causes rampant production of PI(3)P.
To test the potential of MSB, the team used: MTM1 Supplement knockout mice with MSB in their drinking water to deplete PI(3)P levels. This treatment significantly extended lifespan and improved muscle health. “This is a very impressive effect showing the survival of the mice,” Welsh said. “this [XLMTM] model validates [VPS34] This is one of Menadion’s targets. ”
Trotman aims to investigate whether MSB can complement existing treatments for various diseases. He plans to delve deeper into the molecular mechanisms behind pro-oxidant supplements and tryptosis, paving the way for innovative therapeutic strategies.
