J Korean Med Sci.  2016 Mar;31(3):360-370. 10.3346/jkms.2016.31.3.360.

Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation

Affiliations
  • 1Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea. cwkim@korea.ac.kr
  • 2Ministry of Food and Drug Safety, Cheongju, Korea.

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.

Keyword

Cancer Stem Cells; PI3K; mTOR; Drug Resistance; Differentiation Therapy

MeSH Terms

AC133 Antigen/genetics/metabolism
Animals
Antineoplastic Agents/pharmacology/therapeutic use
Cell Differentiation/*drug effects
Cell Line, Tumor
Cell Survival/drug effects
Chromones/pharmacology/therapeutic use
Colorectal Neoplasms/drug therapy/metabolism/pathology
Humans
Imidazoles/pharmacology/therapeutic use
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Morpholines/pharmacology/therapeutic use
Neoplastic Stem Cells/cytology/drug effects/metabolism
Paclitaxel/pharmacology/therapeutic use
Phosphatidylinositol 3-Kinases/*antagonists & inhibitors/metabolism
Quinolines/pharmacology/therapeutic use
SOXB1 Transcription Factors/genetics/metabolism
Signal Transduction/*drug effects
Sirolimus/pharmacology/therapeutic use
TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
Xenograft Model Antitumor Assays
AC133 Antigen
Antineoplastic Agents
Chromones
Imidazoles
Morpholines
Paclitaxel
Phosphatidylinositol 3-Kinases
Quinolines
SOXB1 Transcription Factors
Sirolimus
TOR Serine-Threonine Kinases
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