Abstract
SRC family kinase was documented to have vital roles in adjusting cancer cell malignant behaviors. To date, the role of c-Src, a member of SRC family kinase, in resistance to paclitaxel in human ovarian cancer cells under hypoxia has not been investigated. In the present study, we discovered that hypoxic environment suppressed paclitaxel-induced G2/M phase arrest and blockade of c-Src improved ovarian cancer cells' sensitivity to paclitaxel. FV-429, a derivative of natural flavonoid wogonin, could suppress gene expression and activation of c-Src, followed by deteriorated Stat3 nuclear translocation and its binding to HIF-1α, resulting in paclitaxel resistance reversal through G2/M arrest potentiation. Our study demonstrated that c-Src contributed to hypoxic microenvironment-rendered paclitaxel resistance in human epithelial ovarian cancer cells by G2/M phase arrest deterioration, and through c-Src suppression, FV-429 was capable of reversing the resistance by blocking c-Src/Stat3/HIF-1α pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / adverse effects
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Antineoplastic Agents, Phytogenic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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CSK Tyrosine-Protein Kinase
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Carcinoma, Ovarian Epithelial
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Cell Hypoxia / physiology
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Drug Synergism
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Female
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Flavonoids / administration & dosage
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Flavonoids / adverse effects
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Flavonoids / pharmacology*
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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M Phase Cell Cycle Checkpoints / drug effects
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasms, Glandular and Epithelial / drug therapy*
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Neoplasms, Glandular and Epithelial / metabolism
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Neoplasms, Glandular and Epithelial / pathology
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Paclitaxel / administration & dosage
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Paclitaxel / adverse effects
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Paclitaxel / pharmacology*
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
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src-Family Kinases / metabolism*
Substances
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Antineoplastic Agents, Phytogenic
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FV-429 compound
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Flavonoids
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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STAT3 Transcription Factor
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STAT3 protein, human
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CSK Tyrosine-Protein Kinase
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src-Family Kinases
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CSK protein, human
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Paclitaxel