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Ca<SUP>2</SUP>-activated K<SUP></SUP> Currents of Pancreatic Duct Cells in Guinea-pig
Han-Wook Lee,Jingchao Li,Na-Youn Koo,Zheng Gen Piao,Sung Min Hwang,Jae-Woong Han,Han-Saem Choi,Jong-Heun Lee,Joong Soo Kim,Kyungpyo Park 대한생리학회-대한약리학회 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.6
There are numerous studies on transepithelial transports in duct cells including Cl<SUP></SUP> and/or HCO<SUB>3</SUB><SUP></SUP>. However, studies on transepithelial K<SUP></SUP> transport of normal duct cells in exocrine glands are scarce. In the present study, we examined the characteristics of K<SUP></SUP> currents in single duct cells isolated from guinea pig pancreas, using a whole-cell patch clamp technique. Both Cl<SUP></SUP> and K<SUP></SUP> conductance were found with KCl rich pipette solutions. When the bath solution was changed to low Cl<SUP></SUP>, reversal potentials shifted to the negative side, 75⁑4 mV, suggesting that this current is dominantly selective to K<SUP></SUP>. We then characterized this outward rectifying K<SUP></SUP> current and examined its Ca<SUP>2</SUP> dependency. The K<SUP></SUP> currents were activated by intracellular Ca<SUP>2</SUP>. 100 nM or 500 nM Ca<SUP>2</SUP> in pipette significantly (P<0.05) increased outward currents (currents were normalized, 76.8⁑7.9 pA, n=4 or 107.9⁑35.5 pA, n=6) at 100 mV membrane potential, compared to those with 0 nM Ca<SUP>2</SUP> in pipette (27.8⁑3.7 pA, n=6). We next examined whether this K<SUP></SUP> current, recorded with 100 nM Ca<SUP>2</SUP> in pipette, was inhibited by various inhibitors, including Ba<SUP>2</SUP>, TEA and iberiotoxin. The currents were inhibited by 40.4⁑% (n=3), 87.0⁑% (n=5) and 82.5⁑% (n=9) by 1 mM Ba<SUP>2</SUP>, 5 mM TEA and 100 nM iberiotoxin, respectively. Particularly, an almost complete inhibition of the current by 100 nM iberiotoxin further confirmed that this current was activated by intracellular Ca<SUP>2</SUP>. The K<SUP></SUP> current may play a role in secretory process, since recycling of K<SUP></SUP> is critical for the initiation and sustaining of Cl<SUP></SUP> or HCO<SUB>3</SUB><SUP></SUP> secretion in these cells.
Hwang Yu-Na,Kwon In-Seo,Park Ju-Hee,Na Han-Heom,Kwon Tae-Hyung,Park Jin-Sung,Kim Keun-Cheol 한국유전학회 2023 Genes & Genomics Vol.45 No.12
Background Δ9-Tetrahydrocannabinol (Δ9-THC) is a principal psychoactive extract of Cannabis sativa and has been traditionally used as palliative medicine for neuropathic pain. Cannabidiol (CBD), an extract of hemp species, has recently attracted increased attention as a cancer treatment, but Δ9-THC is also requiring explored pharmacological application. Objective This study evaluated the pharmacological effects of Δ9-THC in two human colorectal cancer cell lines. We investigated whether Δ9-THC treatment induces cell death in human colorectal cancer cells. Methods We performed an MTT assay to determine the pharmacological concentration of Δ9-THC. Annxein V and Western blot analysis confirmed that Δ9-THC induced apoptosis in colorectal cancer cells. Metabolic activity was evaluated using MitoTracker staining and ATP determination. We investigated vesicle formation by Δ9-THC treatment using GW9662, known as a PPARγ inhibitor. Results The MTT assay showed that treatment with 40 μM Δ9-THC and above inhibited the proliferation of colorectal cancer cells. Multiple intracytoplasmic vesicles were detected upon microscopic observation, and fluorescence-activated cell sorting analysis showed cell death via G1 arrest. Δ9-THC treatment increased the expression of cell death marker proteins, including p53, cleaved PARP-1, RIP1, and RIP3, suggesting that Δ9-THC induced the death of colorectal cancer cells. Δ9-THC treatment also reduced ATP production via changes in Bax and Bcl-2. Δ9-THC regulated intracytoplasmic vesicle formation by modulating the expression of PPARγ and clathrin, adding that antiproliferative activity of Δ9-THC was also affected. Conclusion In conclusion, Δ9-THC regulated two functional mechanisms, intracellular vesicle formation and cell death. These findings can help to determine how cannabinoids can be used most effectively to improve the efficacy of cancer treatment.
Ka, Na-Lee,Na, Tae-Young,Na, Hyelin,Lee, Min-Ho,Park, Han-Su,Hwang, Sewon,Kim, Il Yong,Seong, Je Kyung,Lee, Mi-Ock American Association for Cancer Research 2017 Cancer Research Vol.77 No.9
<P>These findings show how a nuclear receptor and its ligands blunts repair of double-strand DNA breaks, suggesting their candidacy as therapeutic targets in cancer patients.</P><P>DNA repair capacity is critical for survival of cancer cells upon therapeutic DNA damage and thus is an important determinant of susceptibility to chemotherapy in cancer patients. In this study, we identified a novel function of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited both nonhomologous end joining and homologous recombination double-strand breaks repair, and delayed the clearance of γH2AX DNA repair foci that formed after treatment of doxorubicin. PARylation of NR1D1 by PARP1 drove its recruitment to damaged DNA lesions. Deletion of the ligand binding domain of NR1D1 that interacted with PARP1, or treatment of 6-(5H)-phenanthridinone, an inhibitor of PARP1, suppressed the recruitment of NR1D1 to DNA damaged sites, indicating PARylation as a critical step for the NR1D1 recruitment. NR1D1 inhibited recruitment of the components of DNA damage response complex such as SIRT6, pNBS1, and BRCA1 to DNA lesions. Downregulation of NR1D1 in MCF7 cells resulted in resistance to doxorubicin, both <I>in vitro</I> and <I>in vivo</I>. Analysis of four public patient data sets indicated that NR1D1 expression correlates positively with clinical outcome in breast cancer patients who received chemotherapy. Our findings suggest that NR1D1 and its ligands provide therapeutic options that could enhance the outcomes of chemotherapy in breast cancer patients. <I>Cancer Res; 77(9); 2453–63. ©2017 AACR</I>.</P>
[$Ca^{2+}-activated\;K^+$ Currents of Pancreatic Duct Cells in Guinea-pig
Lee, Han-Wook,Li, Jing Chao,Koo, Na-Youn,Piao, Zheng Gen,Hwang, Sung-Min,Han, Jae-Woong,Choi, Han-Saem,Lee, Jong-Heun,Kim, Joong-Soo,Park, Kyung-Pyo The Korean Society of Pharmacology 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.6
There are numerous studies on transepithelial transports in duct cells including $Cl^-$ and/or $HCO_3^-$. However, studies on transepithelial $K^+$ transport of normal duct cells in exocrine glands are scarce. In the present study, we examined the characteristics of $K^+$ currents in single duct cells isolated from guinea pig pancreas, using a whole-cell patch clamp technique. Both $Cl^-$ and $K^+$ conductance were found with KCI rich pipette solutions. When the bath solution was changed to low $Cl^-$, reversal potentials shifted to the negative side, $-75{\pm}4\;mV$, suggesting that this current is dominantly selective to $K^+$. We then characterized this outward rectifying $K^+$ current and examined its $Ca^{2+}$ dependency. The $K^+$ currents were activated by intracellular $Ca^{2+}$. 100 nM or 500 nM $Ca^{2+}$ in pipette significantly (P<0.05) increased outward currents (currents were normalized, $76.8{\pm}7.9\;pA$, n=4 or $107.9{\pm}35.5\;pA$, n=6) at +100 mV membrane potential, compared to those with 0 nM $Ca^{2+}$ in pipette $(27.8{\pm}3.7\;pA,\;n=6)$. We next examined whether this $K^+$ current, recorded with 100 nM $Ca^{2+}$ in pipette, was inhibited by various inhibitors, including $Ba^{2+}$, TEA and iberiotoxin. The currents were inhibited by $40.4{\pm}%$ (n=3), $87.0{\pm}%$ (n=5) and $82.5{\pm}%$ (n=9) by 1 mM $Ba^{2+}$, 5 mM TEA and 100 nM iberiotoxin, respectively. Particularly, an almost complete inhibition of the current by 100 nM iberiotoxin further confirmed that this current was activated by intracellular $Ca^{2+}$. The $K^+$ current may play a role in secretory process, slnce recycling of $K^+$ is critical for the initiation and sustaining of $CI^-$ or $HCO_3^-$ secretion in these cells.