title: Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer.
abstract: Cancer stem cells (CSCs) are responsible for aggressive tumor growth, metastasis and therapy resistance. In this study, we evaluated the effects of Shikonin (Shk) on breast cancer and found its anti-CSC potential. Shk treatment decreased the expression of various epithelial to mesenchymal transition (EMT) and CSC associated markers. Kinase profiling array and western blot analysis indicated that Shk inhibits STAT3, FAK and Src activation. Inhibition of these signaling proteins using standard inhibitors revealed that STAT3 inhibition affected CSCs properties more significantly than FAK or Src inhibition. We observed a significant decrease in cell migration upon FAK and Src inhibition and decrease in invasion upon inhibition of STAT3, FAK and Src. Combined inhibition of STAT3 with Src or FAK reduced the mammosphere formation, migration and invasion more significantly than the individual inhibitions. These observations indicated that the anti-breast cancer properties of Shk are due to its potential to inhibit multiple signaling proteins. Shk also reduced the activation and expression of STAT3, FAK and Src in vivo and reduced tumorigenicity, growth and metastasis of 4T1 cells. Collectively, this study underscores the translational relevance of using a single inhibitor (Shk) for compromising multiple tumor-associated signaling pathways to check cancer metastasis and stem cell load.
authors.affiliation: Cell Death Research Laboratory, Endocrinology Division, CSIR-CDRI, Lucknow, INDIA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Thakur
authors.affiliation: Cell Death Research Laboratory, Endocrinology Division, CSIR-CDRI, Lucknow, INDIA.
authors.forename: Rachana
authors.initials: R
authors.lastname: Trivedi
authors.affiliation: Cell Death Research Laboratory, Endocrinology Division, CSIR-CDRI, Lucknow, INDIA.
authors.forename: Namrata
authors.initials: N
authors.lastname: Rastogi
authors.affiliation: Cell Death Research Laboratory, Endocrinology Division, CSIR-CDRI, Lucknow, INDIA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Singh
authors.affiliation: Cell Death Research Laboratory, Endocrinology Division, CSIR-CDRI, Lucknow, INDIA.
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D009285:Naphthoquinones / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D014411:Neoplastic Stem Cells; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004365:Drugs, Chinese Herbal; D009285:Naphthoquinones; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C016101:shikonin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)