title: Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation.
abstract: Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs.
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.; Ministry of Food and Drug Safety, Cheongju, Korea.
authors.forename: Min-Jung
authors.identifier: 0000-0002-5544-8676
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea .
authors.forename: Jeong-Eun
authors.identifier: 0000-0001-6733-2518
authors.initials: JE
authors.lastname: Koo
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea .
authors.forename: Gi-Yeon
authors.identifier: 0000-0001-9825-169X
authors.initials: GY
authors.lastname: Han
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea .
authors.forename: Buyun
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea .
authors.forename: Yoo-Sun
authors.identifier: 0000-0002-2258-6749
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Ministry of Food and Drug Safety, Cheongju, Korea .
authors.forename: Chiyoung
authors.identifier: 0000-0002-3747-0175
authors.initials: C
authors.lastname: Ahn
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea .
authors.forename: Chan-Wha
authors.identifier: 0000-0003-2329-8834
authors.initials: CW
authors.lastname: Kim
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D000970:Antineoplastic Agents; D002867:Chromones; D007093:Imidazoles; D009025:Morpholines; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D055748:SOXB1 Transcription Factors; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C527782:SOX2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human; C531198:dactolisib
keywords: Cancer Stem Cells; Differentiation Therapy; Drug Resistance; PI3K; mTOR