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Purpose: Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of patients with depression. Approximately 60% of women with breast cancer suffer from depression. This study was performed to investigate the effect of SSRIs on cell viability of human breast cancer MCF-7 cells. Methods: Cell viability, ROS generation, and Ca2+ increase were quantified using MTT, H2DCFDA, and Fluo-3 AM. Apoptotic signaling pathways were analyzed by immuno-blotting and -staining. Plasma and mitochondrial membrane potentials were determined by DiO PMP and JC-1 dyes, respectively. K+ channel activity was analyzed by whole-cell and single-channel recordings. Results: Of the antidepressants tested in this study, paroxetine most reduced the viability of MCF-7 cells. Paroxetine (10 and 30 μM) treatment resulted in a significant increase in the number of apoptotic cells, an increase in Bax/Bcl-2 ratio, an activation of caspase-8, 9, and PARP, and a release of cytochrome c from mitochondria. In addition, paroxetine markedly increased ROS generation and intracellular Ca2+ levels. Moreover, paroxetine blocked K+ channels, such as large conductance Ca2+-activated K+ channel and TASK-3 channel, which are present in plasma membrane and mitochondria. The paroxetine-induced apoptosis was reduced by antioxidants, in particular NAC. Combination with SB202190 (a p38 MAPK inhibitor) prevented cells from undergoing apoptosis. Conclusion: Our findings show that apoptotic effect of paroxetine is mediated by mitochondrial dysfunction and modulation of K+ channels in MCF-7 cells. We suggest that paroxetine could be an agent for anti-tumor therapy in breast cancer. Citation Format: Kee R. Kang, Young-Woo Cho, Ji Hyun Ryu, Eun-Jin Kim, Jaehee Han, Dawon Kang. Paroxetine induces apoptosis in human breast cancer MCF-7 cells through mitochondrial dysfunction and modulation of K+ channels. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3519.

Precursor B lymphoblastic leukemia is a B-cell lineage neoplasm of lymphoblasts. The initial response to induction-chemotherapy is the most important prognostic factor in acute lymphoblastic leukemia (ALL) patients. Patients with rapid-early-response (RER, below 5% of blast in bone marrow at day-7 after induction-chemotherapy) have better event-free survival compared to slow-early-responders (SER, above 25% of blast). The drug sensitivity/resistance of leukemic blasts is mainly determined by specific genetic abnormalities, however, in more than 20% of ALL, the abnormalities remain unclassified, and the treatment outcome persist variable. This study aimed to find plausible biomarkers of drug sensitivity/resistance in ALL using proteomic analysis. We identified 28 up-regulated and 25 down-regulated proteins in SER_as compared to RER_by MALDI-TOF and mass spectrometry. Of these, 14-3-3 isoforms and cytoskeletal proteins were differentially expressed. Alpha tubulin and 14-3-3 gamma, down-regulated in RER were further verified by Western blot analysis. In further studies, the roles of these proteins in drug sensitivity/resistance are undergoing to elucidate as a potential biomarker for ALL therapy. Citation Format: Kee R. Kang, Eun Sil Park. Differential expression of cytoskeletal proteins in acute lymphoblastic leukemia in accordance with initial response to chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2503. doi:10.1158/1538-7445.AM2014-2503

Colorectal cancer (CRC) is the third most prevalent cancer worldwide and has poor prognosis. Recent improvement in methods for proteome analysis has offered the possibility of identifying disease-associated protein markers to assist in diagnosis or prognosis, and for selecting potential targets for specific drug therapy. In current study, the proteome of colorectal adenocarcinoma and the corresponding normal tissues was visualized and analyzed a number of proteins to isolate and identify tumor-specific proteins for CRC. Ten proteins were dominantly expressed and five proteins were largely repressed in CRC by the analysis of 2-DE and MALDI-TOF/mass spectrometry. Ubiquitin conjugating enzyme E2N, one of enzyme necessary for ubiquitination, and proteasome activator complex subunit 3 were focused to be increased in CRC tissues compared with normal colorectal tissues. The elevated expression of E2N and proteasome activator complex subunit 3 in CRC was confirmed by Western blot analysis and real time PCR. Immunohistochemistry also verified largely up-regulation of E2N and proteasome activator complex subunit 3 in 85 CRC patients. These findings suggest that ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3, which are involved in the ubiquitin-proteasome system, could be possible tumor biomarker candidates in CRC tissues. [Funding source: NRF grant (R13-2005-012-01003-0)]. Citation Format: Kee R. Kang, Jung H. Kang, Young-Tae Ju. Proteomic identification of ubiquitin conjugating enzyme E2N and proteasome activator complex subunit 3 as potential biomarkers in colorectal cancer tissues. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2484. doi:10.1158/1538-7445.AM2013-2484

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biological and prognostic grouping. The initial response to induction chemotherapy is the most important prognostic factor in patients with acute lymphoblastic leukemia. Patients with rapid early response (RER < 5% of blast in bone marrow at day 7 after induction chemotherapy) have better event-free survival compared to slow early responders (SER ≤ 25% of blast). However, no predictive marker for relapse or treatment failure is currently available. This study aimed to find plausible biomarkers of drug sensitivity in bone marrow mononuclear cells (BMMNCs) of childhood ALL cases using 2-dimensional gel electrophoresis and subsequent MALDI-TOF/mass spectrometry. The 714 spots in RER and 555 spots in SER were visualized in gels. Of these 28 up-regulated and 25 down-regulated proteins in SER_as compared to RER_were identified. The detected proteins were 60-kDa heat shock protein, actin, lamin-B1, heterogeneous nuclear ribonucleoprotein (hnRNP) K, and so on. HnRNPK, down-regulated in SER was further verified by Western blot analysis. In future studies, the roles of HnRNPK in drug sensitivity/resistance are undergoing to elucidate as a potential biomarker for ALL therapy. [Funding source: NRF grant (R13-2005-012-01003-0)]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4783. doi:1538-7445.AM2012-4783

Colorectal cancer is one of the most prevalent tumors in developed countries, and the best characterized cancers with regard to genetic progression of disease. Recent improvement in methods for proteome analysis has offered the possibility of identifying disease-associated protein markers to assist in diagnosis or prognosis, and for selecting potential targets for specific drug therapy. For identification and targeting of tumor-associated marker proteins, the proteome of colorectal adenocarcinoma (CRC) and normal colorectal tissues was analyzed by 2-DE. Inosine monophosphate dehydrogenase type 2 (IMPDH2), a key enzyme of de novo purine nucleotide biosynthesis, was identified by MALDI-TOF/MS and found to be expressed at high rates in the colorectal tumor tissues. We found an increased amount of IMPDH2 mRNA in CRC compared to that observed in the normal colorectal tissues by Northern blot. Real time PCR analysis in both tissues also revealed the higher expression of IMPDH2 mRNA in CRC. Western blot analysis was carried out to confirm the elevated expression of protein level for IMPDH2 in CRC compared with normal tissues. Immunohistochemical studies denoted that tumor tissues showed higher N/C ratio, abnormal shape of gland, and darker staining in glandular area. In addition, using in situ hybridization, it was demonstrated the expression of IMPDH2 in CRC tissues was extremely high in the vicinity of mucosal gland, while IMPDH2 in the normal colorectal tissues was evenly distributed in all tissue area with lower level. These findings suggest that IMPDH2 could be a possible tumor biomarker candidate in CRC tissues. This study was supported by KOSEF grant (R13-2005-012-01003-0) and KRF grants (2006-005-J04203). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5558.