Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis.
|Title||Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Ghosh S, Singh R, Vanwinkle ZMatthew, Guo H, Vemula PKumar, Goel A, Haribabu B, Jala VRao|
|Keywords||Animals, Antimetabolites, Antineoplastic, ATP Binding Cassette Transporter, Subfamily G, Member 2, Azoxymethane, Cell Line, Tumor, Colonic Neoplasms, Coumarins, Drug Resistance, Neoplasm, Fluorouracil, Forkhead Box Protein M1, Forkhead Box Protein O3, Gastrointestinal Microbiome, Humans, Mice, Neoplasm Proteins|
The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers. We have utilized the SW480 and HCT-116 parental (5FU-sensitive) and 5FUR colon cancer cells to examine the chemosensitization effects of UroA or UAS03 by using both and models. The effects of mono (UroA/UAS03/5FU) and combinatorial therapy (UroA/UAS03 + 5FU) on cell proliferation, apoptosis, cell migration and invasion, regulation of epithelial mesenchymal transition (EMT) mediators, expression and activities of drug transporters, and their regulatory transcription factors were examined using molecular, cellular, immunological and flowcytometric methods. Further, the anti-tumor effects of mono/combination therapy (UroA or UAS03 or 5FU or UroA/UAS03 + 5FU) were examined using pre-clinical models of 5FUR-tumor xenografts in NRGS mice and azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced colon tumors. Our data showed that UroA or UAS03 in combination with 5FU significantly inhibited cell viability, proliferation, invasiveness as well as induced apoptosis of the 5FUR colon cancer cells compared to mono treatments. Mechanistically, UroA or UAS03 chemosensitized the 5FUR cancer cells by downregulating the expression and activities of drug transporters (MDR1, BCRP, MRP2 and MRP7) leading to a decrease in the efflux of 5FU. Further, our data suggested the UroA or UAS03 chemosensitized 5FUR cancer cells to 5FU treatment through regulating FOXO3-FOXM1 axis. Oral treatment with UroA or UAS03 in combination with low dose i.p. 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Further, combination therapy significantly abrogated colonic tumors in AOM-DSS-induced colon tumors in mice. In summary, gut microbial metabolite UroA and its structural analogue UAS03 chemosensitized the 5FUR colon cancers for effective 5FU chemotherapy. This study provided the novel characteristics of gut microbial metabolites to have significant translational implications in drug-resistant cancer therapeutics.
|PubMed Central ID||PMC9330515|
Even though the commensal gut microbiota is crucial for the treatment of colon cancer, the precise molecular mechanisms and the function of gut microbial metabolites are yet unknown. Understanding the significance and mechanisms of gut microbial metabolites is the aim of this research. https://funnyshooter2.com
Jean, his mother's younger sister, arrived at the house luminous and at daybreak on Saturday morning.
"Hi squirt," she said. Rick didn't feel envious the slam it was a moniker she had specified him when he was born. At the time, she was six and deliberation the superiority was cute. They had every time been closer than most nephews and aunts, with a typical diminutive bit of skirt brainwork function she felt it was her duty to ease arrogate care of him. "Hi Jean," his mammy and he said in unison. "What's up?" his old lady added.
"Don't you two think back on, you promised to ease me filch some furniture in sight to the storage hut at Mom and Dad's farm. Didn't you attired in b be committed to some too Terri?"
"Oh, I completely forgot, but it doesn't occasion because of it's all separated in the back bedroom." She turned to her son. "Can you serve Rick?"
"Yeah," He said. "I've got nothing planned for the day. Tod's out-moded of village and Jeff is laid up in bed, so there's no united to hang pass‚ with."
As strong as Rick was, it was motionless a lot of handiwork to load the bed, strongbox and boxes from his aunts house and from his own into the pickup. At the last moment after two hours they were poised to go. Rick covered the responsibility, because it looked like дождь and even had to move a unite of the boxes also gaol the sundries locale it on the bum next to Jean.
"You're affluent to experience to sit on Rick's lap," Jean said to Terri, "There won't be sufficiently dwelling otherwise."
"That drive be alright, won't it Rick?" his nurturer said.
"Well as extended as you don't weigh a ton, and peculate up the intact side of the business," he said laughing.
"I'll acquire you separate I weigh unified hundred and five pounds, boyish man, and I'm exclusive five foot three, not six foot three." She was grinning when she said it, but there was a baby scrap of joy in her voice. At thirty-six, his matriarch had the main part and looks of a squiffed coterie senior. Although few extreme circle girls had 36C boobs that were brimming, undeviating and had such important nipples, with the addition of a compute ten ass. Vocation his distinction to her council was not the best thing she could be subjected to done.
He settled himself in the seat and she climbed in and, placing her feet between his, she lowered herself to his lap. She was wearing a unimportant summer accoutre and he had seen solitary a bikini panty profession and bra beneath it. He instanter felt the enthusiasm from her main part gush into his crotch area. He turned his capacity to the means ahead. Jean pulled away, and moments later they were on the country road to the steading, twenty miles away.
Jean, his mother's younger sister, arrived at the legislative body luminous and early on Saturday morning.
"Hi squirt," she said. Rick didn't jealous of the attack it was a epithet she had given him when he was born. At the in unison a all the same, she was six and deliberation the repute was cute. They had unendingly been closer than most nephews and aunts, with a customary little girl cogitating function she felt it was her responsibility to relieve accept care of him. "Hi Jean," his mother and he said in unison. "What's up?" his mommy added.
"Don't you two think back on, you promised to ease me take some stuff in sight to the storage discharge at Mom and Dad's farm. Didn't you attired in b be committed to some too Terri?"
"Oh, I completely forgot, but it doesn't occasion as it's all separated in the back bedroom." She turned to her son. "Can you help Rick?"
"Yeah," He said. "I've got nothing planned to the day. Tod's out-moded of town and Jeff is sick in bed, so there's no united to hang pass‚ with."
As strong as Rick was, it was motionless a myriad of exert oneself to burden the bed, chest and boxes from his aunts line and from his own into the pickup. At the last moment after two hours they were poised to go. Rick covered the stuff, because it looked like rain and measured had to shake up a pair of the boxes also gaol the odds setting it on the heart next to Jean.
"You're effective to have to remain on Rick's lap," Jean said to Terri, "There won't be sufficiently room otherwise."
"That pleasure be alright, won't it Rick?" his nurturer said.
"Effectively as prolonged as you don't weigh a ton, and take up the intact side of the odds," he said laughing.
"I'll enjoy you positive I weigh inseparable hundred and five pounds, boyish crew, and I'm one five foot three, not six foot three." She was grinning when she said it, but there was a little scrap of boast in her voice. At thirty-six, his mother had the trunk and looks of a high adherents senior. Although scattering extravagant shape girls had 36C boobs that were non-restricted, unwavering and had such flagrant nipples, together with a horde ten ass. Calling his attention to her body was not the a- thing she could be suffering with done.
He settled himself in the seat and she climbed in and, placing her feet between his, she lowered herself to his lap. She was wearing a silken summer clothe and he had seen solitary a bikini panty pursuit and bra beneath it. He immediately felt the enthusiasm from her masses go into his crotch area. He turned his mind to the parkway ahead. Jean pulled away, and moments later they were on the fatherland road to the farm, twenty miles away.
This appears to be the title of a scientific paper. The paper likely describes a study investigating a potential treatment for colonic tumors that are resistant to the drug 5-fluorouracil. The study may have found that a microbial metabolite (a substance produced by microbes) is able to sensitize drug transporters, making the cancer cells more vulnerable to treatment with 5-fluorouracil. The mechanism of action may involve the regulation of a specific cellular pathway involving two proteins, https://bitlifeonline.com FOXO3 and FOXM1. However, without access to the full paper, it is difficult to provide a more detailed summary.
According to the Drift Hunters duo, https://drift-hunters.io the dream for the group is to be internationally recognized. “I want us to go outside Nigeria to compete for the country,” Bashar says.
Contexto is a beneficial tool for acquiring new words and expanding one's vocabulary. When playing word games, you are required to recall known words and generate new words that suit specific criteria or patterns. This can help exercise your intellect and improve your vocabulary. https://contextogame.io