title: PAC exhibits potent anti-colon cancer properties through targeting cyclin D1 and suppressing epithelial-to-mesenchymal transition.
abstract: Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide. Although response rates and overall survival have been improved in recent years, resistance to multiple drug combinations is inevitable. Therefore, the development of more efficient drugs, with fewer side effects is urgently needed. To this end, we have investigated in the present report the effect of PAC, a novel cucumin analogue, on CRC cells both in vitro and in vivo. We have shown that PAC induces apoptosis, mainly via the internal mitochondrial route, and inhibits cell proliferation through delaying the cell cycle at G2/M phase. Interestingly, the pro-apoptotic effect was mediated through STAT3-dependent down-regulation of cyclin D1 and its downstream target survivin. Indeed, change in the expression level of cyclin D1 modulated the expression of survivin and the response of CRC cells to PAC. Furthermore, using the ChIP assay, we have shown PAC-dependent reduction in the binding of STAT3 to the cyclin D1 promoter in vivo. Additionally, PAC suppressed the epithelial-to-mesenchymal process through down-regulating the mesenchymal markers (N-cadherin, vimentin and Twist1) and inhibiting the invasion/migration abilities of the CRC cells via repressing the pro-migration/invasion protein kinases AKT and ERK1/2. In addition, PAC inhibited tumor growth and repressed the JAK2/STAT3, AKT/mTOR and MEK/ERK pathways as well as their common downstream effectors cyclin D1 and survivin in humanized CRC xenografts. Collectively, these results indicate that PAC has potent anti-CRC effects, and therefore could constitute an effective alternative chemotherapeutic agent, which may consolidate the adjuvant treatment of colon cancer.
authors: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Abeer
authors: A
authors: Al-Qasem
authors: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Huda A
authors: HA
authors: Al-Howail
authors: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Mashael
authors: M
authors: Al-Swailem
authors: Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Amer
authors: A
authors: Al-Mazrou
authors: Department of Cyclotron and Radiopharmaceuticals, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Basem
authors: B
authors: Al-Otaibi
authors: Department of Cyclotron and Radiopharmaceuticals, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Ibrahim
authors: I
authors: Al-Jammaz
authors: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|The Joint Center for Genomics Research, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors: Huda H
authors: HH
authors: Al-Khalaf
authors: Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Abdelilah
authors: A
authors: Aboussekhra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D019938:Cyclin D1 / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008819:Mice, Nude; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D003474:Curcumin
keywords: Cyclin D1; EMT; PAC; STAT3; colorectal cancer