Hypoxia Promotes Synergy between Mitomycin C and Bortezomib through a Coordinated Process of Bcl-xL Phosphorylation and Mitochondrial Translocation of p53

Song, Xinxin,Dilly, Ashok-Kumar,Choudry, Haroon Asif,Bartlett, David L.,Kwon, Yong Tae,Lee, Yong J. American Association for Cancer Research 2015 Molecular Cancer Research Vol.13 No.12

<P>Colorectal peritoneal carcinomatosis (CPC) exhibits severe tumor hypoxia, leading to drug resistance and disease aggressiveness. This study demonstrates that the combination of the chemotherapeutic agent mitomycin C with the proteasome inhibitor bortezomib induced synergistic cytotoxicity and apoptosis, which was even more effective under hypoxia in colorectal cancer cells. The combination of mitomycin C and bortezomib at sublethal doses induced activation of c-Jun NH<SUB>2</SUB>-terminal kinase and p38 mitogen-activated protein kinase and resulted in Bcl-xL phosphorylation at Serine 62, leading to dissociation of Bcl-xL from proapoptotic Bak. Interestingly, the intracellular level of p53 became elevated and p53 translocated to the mitochondria during the combinatorial treatment, in particular under hypoxia. The coordinated action of Bcl-xL phosphorylation and p53 translocation to the mitochondria resulted in conformational activation of Bak oligomerization, facilitating cytochrome <I>c</I> release and apoptosis induction. In addition, the combinatorial treatment with mitomycin C and bortezomib significantly inhibited intraperitoneal tumor growth in LS174T cells and increased apoptosis, especially under hypoxic conditions <I>in vivo</I>. This study provides a preclinical rationale for the use of combination therapies for CPC patients.</P><P><B>Implications:</B> The combination of a chemotherapy agent and proteasome inhibitor at sublethal doses induced synergistic apoptosis, in particular under hypoxia, <I>in vitro</I> and <I>in vivo</I> through coordinated action of Bcl-xL and p53 on Bak activation. <I>Mol Cancer Res; 13(12); 1533–43. ©2015 AACR</I>.</P>

Crosstalk Between Apoptosis and Autophagy Is Regulated by the Arginylated BiP/Beclin-1/p62 Complex

Song, Xinxin,Lee, Dae-Hee,Dilly, Ashok-Kumar,Lee, Young-Sun,Choudry, Haroon Asif,Kwon, Yong Tae,Bartlett, David L.,Lee, Yong J. American Association for Cancer Research 2018 Molecular Cancer Research Vol.16 No.7

<P>Emerging evidence demonstrates that autophagy and apoptosis are interconnected and their interplay greatly affects cell death. However, the key regulators in this crosstalk remain elusive. Therefore, the role of N-terminal arginylated BiP (R-BiP)/Beclin-1/p62 complex was examined in the crosstalk between apoptosis and autophagy during combination chemotherapy with mitomycin C and bortezomib using immunoblot, immunoprecipitation, and cellular imaging assays in wild-type (WT) and genetically engineered colorectal cancer cells. In addition, the tumoricidal efficacy of the combinatorial treatment in a nude mouse tumor xenograft model of colorectal cancer was assessed. Bortezomib combined with mitomycin C synergistically induced cytotoxicity and apoptosis rather than autophagy. Mechanistically, this combination inactivated Akt and subsequently induced Beclin-1 (<I>BECN1</I>) dephosphorylation at Ser 234/295. Dephosphorylation of Beclin-1 resulted in increased cleavage of Beclin-1 and disruption of the R-BiP/Beclin-1/p62 complex, which led to switching autophagy to the synergistic induction of apoptosis. Importantly, the combination significantly suppressed LS174T intraperitoneal xenograft tumor growth, induced Akt inactivation and Beclin-1 cleavage, and decreased autophagy <I>in vivo</I>. Moreover, the tumoricidal efficacy of the combinatorial treatment was less effective, <I>in vitro</I> and <I>in vivo</I>, in HCT116 tumors harboring a Beclin-1 caspase 8 cleavage site mutant knock-in.</P><P><B>Implications:</B> This study uncovers that the R-BiP/Beclin-1/p62 complex has an important role in the crosstalk between apoptosis and autophagy. The results also propose how mono-drug resistance can be overcome using potent combinations to improve anticancer therapy. <I>Mol Cancer Res; 16(7); 1077–91. ©2018 AACR</I>.</P>

Physical Changes in Satsuma Mandarin Leaf after Infection of Elsinoë fawcettii Causing Citrus Scab Disease

Dilli Prasad Paudyal,현재욱 한국식물병리학회 2015 Plant Pathology Journal Vol.31 No.4

Citrus scab disease is one of the destructive diseases that reduce the value of fruit for the fresh market. We analyzed the process of symptom development after infection with scab pathogen Elsinoë fawcettii in the susceptible satsuma mandarin leaves to observe the structural modification against pathogen. The cuticle and epidermal cells along with 3–5 layers of mesophyll tissue were degraded 1–2 days post inoculation. Surrounding peripheral cells of degraded tissues grew rapidly and then enveloped the necrotic area along with the growing conidia. Cross sections through the lesion revealed hyphal colonization in epidermis and mesophyll tissues. In response to the pathogen colonization, host cell walls were lignified, inner cells were rapidly compartmentalized and a semi-circular boundary was formed that separated the infected region from the non-infected region, and finally prevented the intercellular pathogen spread.

Lack of any Prognostic Role of Insulin-Like Growth Factor-1 Receptor in Non-Small Cell Lung Cancer

Dilli, Utku Donem,Yildırim, Mustafa,Suren, Dinc,Alikanoglu, Arsenal,Kaya, Vildan,Goktas, Sevil,Yildiz, Mustafa,Sezer, Cem,Gunduz, Seyda Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.14

Background: The purpose of this study is to determine whether the IGF1R expression has a prognostic role in non-small cell lung cancer. Materials and Methods: Forty-seven patients histopathologically diagnosed with small cell lung cancer upon bronchoscopic biopsy or resection materials were included in the study. IGF1R expression was examined via immunohistochemical methods. In samples, >10% staining were assessed as positive and ${\leq}10%$ as negative. Information about demographic datas and treatments was obtained by retrospective searches of patient files. Results: IGF1R expression was determined as positive in 38 (80.9%) and as negative in 9 (19.1%) patients. There was no significant relation between IGF1R expression and histological sub-type, local invasion, lymph node and metastasis status (p=0.842, p=0.437, 0.064, 0.447, respectively). There was also no correlation with IGF1R expression and survival (p=0.141). Conclusions: There are conflicting results between IGF1R and its prognostic effects in the various studies. It has been claimed in some studies it is not related to prognosis as in our study, and in some studies it has been claimed that it is a good prognostic factor whereas in some studies it has been claimed as being a factor for worse prognosis. We think that IGF1R expression in non-small cell lung carcinoma patients deserves further analysis, because of its potential prognostic and predictive roles.

Ancient Life in Far west Nepal in 21st Century

Dilli Prasad Jaishi 한국물학회 2017 한국물학회지 Vol.6 No.1

Far-West Nepal is naturally beautiful and life is beautiful here. The culture is rich and relatively untouched, from the nomadic Rautes to the Rana Tharu, who travelled all the way from Rajasthan when the Moghuls invaded India. About 300 Km western from mountain area of Far west Nepal the life in Terai village is different. Every village here gives us experience of different feel with the maturity of the ethnic tribe lives. Tharu peopleare anethnic groupindigenousto the southern foothills of theHimalayas. Tharus here have their old culture and customs. Tharu community usually catches fish for food founding rivers. They prepare different dishes from fish. Shakhiya, Humra, Hutunguwa and Kathariya dances are main attraction of ancient salivations. The dress worn by them are typical and called Lehenga which is the ancient customs. Plough, Yoke, Leveler, Harrow, Mallot are the tillage implements tools of farmers. Khilna, Kudali are the intercultural operation tools of farmers. Sickle is the main harvesting tools. Wooden Pin, wooden pole, suhaga, bamboo basket(Kilta), tokri, hand mill (Jutaro/Jato), water mill (ghatta), winnower, sieve, sack, shearer, skinner and pineare the post harvest tools and implements. These are the ancient tools of agriculture system of farmers in far west Nepal still using. The ancient life in far west Nepal is the attraction to the world community where they can have unique experience of ancient life with all culture and customs in far west Nepal. To accomplish the different feel of every village in short time, the far west Nepal is an idol destination for experiencing the feeling of ancient life.

Biological Effect and Chemical Composition Variation During Self-Fermentation of Stored Needle Extracts from Pinus densiflora Siebold & Zucc.

정현숙,Dilli P. Paudyal,Gayoung Park,황인덕,Kim Dong-Woon 한국식물생명공학회 2007 JOURNAL OF PLANT BIOTECHNOLOGY Vol.34 No.4

Extract of Japanese red pine needles has been used in Asia pacific regions since long periods believing its valuable properties as tonic and ability of curing diseases of unidentified symptoms. Some selective compounds present in the extract and their effects were analyzed. Carbohydrates and vitamin c were identified using HPLC; terpenoid compounds by GC-MS; anti-bacterial analysis by paper discs, plates count and gastrointestinal motility by whole cell patch clamp. The extract is a mixture of compounds therefore its diverse effect was expected. Self-fermentation in extract proceeds after spontaneous appearance of yeast strains without inoculation. Effects and composition of the extract vary with varying period of self-fermentation. Extract inhibits the growth of bacteria dose dependently exhibiting its antibacterial properties however effectiveness increases with increase in fermentation period. The extract also can modulate gastrointestinal motility in murine small intestine by modulating pace maker currents in ICC mediated through ATP sensitive potassium channel.

Infection and symptom development by citrus scab pathogen Elsinoë fawcettii on leaves of satsuma mandarin

Paudyal, Dilli Prasad,Hyun, Jae-Wook,Hwang, Rok-Yeun Springer-Verlag 2017 European journal of plant pathology Vol.148 No.4

Physical Changes in Satsuma Mandarin Leaf after Infection of Elsinoë fawcettii Causing Citrus Scab Disease

Paudyal, Dilli Prasad,Hyun, Jae-Wook The Korean Society of Plant Pathology 2015 Plant Pathology Journal Vol.31 No.4

Citrus scab disease is one of the destructive diseases that reduce the value of fruit for the fresh market. We analyzed the process of symptom development after infection with scab pathogen $Elsino{\ddot{e}}$ fawcettii in the susceptible satsuma mandarin leaves to observe the structural modification against pathogen. The cuticle and epidermal cells along with 3-5 layers of mesophyll tissue were degraded 1-2 days post inoculation. Surrounding peripheral cells of degraded tissues grew rapidly and then enveloped the necrotic area along with the growing conidia. Cross sections through the lesion revealed hyphal colonization in epidermis and mesophyll tissues. In response to the pathogen colonization, host cell walls were lignified, inner cells were rapidly compartmentalized and a semi-circular boundary was formed that separated the infected region from the non-infected region, and finally prevented the intercellular pathogen spread.

The regulatory role of c-MYC on HDAC2 and PcG expression in human multipotent stem cells

Bhandari, Dilli Ram,Seo, Kwang-Won,Jung, Ji-Won,Kim, Hyung-Sik,Yang, Se-Ran,Kang, Kyung-Sun Blackwell Publishing Ltd 2011 JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Vol.15 No.7

<P><B>Abstract</B></P><P>Myelocytomatosis oncogene (c-MYC) is a well-known nuclear oncoprotein having multiple functions in cell proliferation, apoptosis and cellular transformation. Chromosomal modification is also important to the differentiation and growth of stem cells. Histone deacethylase (HDAC) and polycomb group (PcG) family genes are well-known chromosomal modification genes. The aim of this study was to elucidate the role of c-MYC in the expression of chromosomal modification <I>via</I> the HDAC family genes in human mesenchymal stem cells (hMSCs). To achieve this goal, c-MYC expression was modified by gene knockdown and overexpression <I>via</I> lentivirus vector. Using the modified c-MYC expression, our study was focused on cell proliferation, differentiation and cell cycle. Furthermore, the relationship of c-MYC with HDAC2 and PcG genes was also examined. The cell proliferation and differentiation were checked and shown to be dramatically decreased in c-MYC knocked-down human umbilical cord blood-derived MSCs, whereas they were increased in c-MYC overexpressing cells. Similarly, RT-PCR and Western blotting results revealed that HDAC2 expression was decreased in c-MYC knocked-down and increased in c-MYC overexpressing hMSCs. Database indicates presence of c-MYC binding motif in HDAC2 promoter region, which was confirmed by chromatin immunoprecipitation assay. The influence of c-MYC and HDAC2 on PcG expression was confirmed. This might indicate the regulatory role of c-MYC over HDAC2 and PcG genes. c-MYCs’ regulatory role over HDAC2 was also confirmed in human adipose tissue-derived MSCs and bone-marrow derived MSCs. From this finding, it can be concluded that c-MYC plays a vital role in cell proliferation and differentiation <I>via</I> chromosomal modification.</P>

Biological Effect and Chemical Composition Variation During Self-Fermentation of Stored Needle Extracts from Pinus densiflora Siebold & Zucc.

Paudyal, Dilli P.,Park, Ga-Young,Hwang, In-Deok,Kim, Dong-Woon,Cheong, Hyeon-Sook The Korean Society of Plant Biotechnology 2007 식물생명공학회지 Vol.34 No.4

Extract of Japanese red pine needles has been used in Asia pacific regions since long periods believing its valuable properties as tonic and ability of curing diseases of unidentified symptoms. Some selective compounds present in the extract and their effects were analyzed. Carbohydrates and vitamin c were identified using HPLC; terpenoid compounds by GC-MS; anti-bacterial analysis by paper discs, plates count and gastrointestinal motility by whole cell patch clamp. The extract is a mixture of compounds therefore its diverse effect was expected. Self-fermentation in extract proceeds after spontaneous appearance of yeast strains without inoculation. Effects and composition of the extract vary with varying period of self-fermentation. Extract inhibits the growth of bacteria dose dependently exhibiting its antibacterial properties however effectiveness increases with increase in fermentation period. The extract also can modulate gastrointestinal motility in murine small intestine by modulating pace maker currents in ICC mediated through ATP sensitive potassium channel.