Cyclophilin B induces chemoresistance by degrading wild‐type p53 via interaction with MDM2 in colorectal cancer

Choi, Tae Gyu,Nguyen, Minh Nam,Kim, Jieun,Jo, Yong Hwa,Jang, Miran,Nguyen, Ngoc Ngo Yen,Yun, Hyeong Rok,Choe, Wonchae,Kang, Insug,Ha, Joohun,Tang, Dean G,Kim, Sung Soo John Wiley Sons, Ltd 2018 The Journal of pathology Vol.246 No.1

<P><B>Abstract</B></P><P>Colorectal cancer (CRC) is one of the leading causes of cancer‐related deaths worldwide. Chemoresistance is a major problem for effective therapy in CRC. Here, we investigated the mechanism by which peptidylprolyl isomerase B (PPIB; cyclophilin B, CypB) regulates chemoresistance in CRC. We found that CypB is a novel wild‐type p53 (p53WT)‐inducible gene but a negative regulator of p53WT in response to oxaliplatin treatment. Overexpression of CypB shortens the half‐life of p53WT and inhibits oxaliplatin‐induced apoptosis in CRC cells, whereas knockdown of CypB lengthens the half‐life of p53WT and stimulates p53WT‐dependent apoptosis. CypB interacts directly with MDM2, and enhances MDM2‐dependent p53WT ubiquitination and degradation. Furthermore, we firmly validated, using bioinformatics analyses, that overexpression of CypB is associated with poor prognosis in CRC progression and chemoresistance. Hence, we suggest a novel mechanism of chemoresistance caused by overexpressed CypB, which may help to develop new anti‐cancer drugs. We also propose that CypB may be utilized as a predictive biomarker in CRC patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</P>

Epigenetic Therapies as a Promising Strategy for Overcoming Chemoresistance in Epithelial Ovarian Cancer

서동훈,김희승,김미경,정현훈,송용상 대한암예방학회 2013 Journal of cancer prevention Vol.18 No.3

Over the past decades, prognosis of advanced stage epithelial ovarian cancer remains very poor, despite the development of new chemotherapeutic drugs, as well as molecular targeted agents. Late presentation and frequent chemoresistance account for the poor prognosis. Emerging studies have shown that many genetic changes, especially p53 mutation, are associated with the chemoresistance. However, recent failure of the clinical trials using p53 gene-therapy makes researchers discuss the possible reasons for the failure. Epigenetic changes are considered one of the substantial reasons. Successful restoration of the aberrant epigenetic changes may be a promising strategy for overcoming chemoresistance in epithelial ovarian cancer. Herein, we will summarize the rationale for epigenetic therapy of cancer and current status of epigenetic studies in relation to chemoresistance in epithelial ovarian cancer.

Mechanisms of resistance to chemotherapy in non-small cell lung cancer

민혜영,이호영 대한약학회 2021 Archives of Pharmacal Research Vol.44 No.2

Non-small cell lung cancer (NSCLC), whichrepresents 80–85% of lung cancer cases, is one of the leadingcauses of human death worldwide. The majority ofpatients undergo an intensive and invasive treatment regimen,which may include radiotherapy, chemotherapy, targetedtherapy, immunotherapy, or a combination of these,depending on disease stage and performance status. Despiteadvances in therapeutic regimens, the 5-year survival ofNSCLC is approximately 20–30%, largely due to diagnosisat advanced stages. Conventional chemotherapy is stillthe standard treatment option for patients with NSCLC,especially those with advanced disease. However, the emergenceof resistance to chemotherapeutic agents (chemoresistance)poses a signifi cant obstacle to the managementof patients with NSCLC. Therefore, to develop effi caciouschemotherapeutic approaches for NSCLC, it is necessaryto understand the mechanisms underlying chemoresistance. Several mechanisms are known to mediate chemoresistance. These include altered cellular targets for chemotherapy,decreased cellular drug concentrations, blockadeof chemotherapy-induced cell cycle arrest and apoptosis,acquisition of epithelial–mesenchymal transition and cancerstem cell-like phenotypes, deregulated expression ofmicroRNAs, epigenetic modulation, and the interaction withtumor microenvironments. In this review, we summarize the mechanisms underlying chemoresistance and tumor recurrencein NSCLC and discuss potential strategies to avoid orovercome chemoresistance.

The Diarylheptanoid Hirsutenone Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin via Modulation of Apoptosis-inducing Factor and X-linked Inhibitor of Apoptosis

Farrand, Lee,Kim, Ji Young,Byun, Sanguine,Im-aram, Akechai,Lee, Jihoon,Suh, Jeong-Yong,Lee, Ki-Won,Lee, Hyong Joo,Tsang, Benjamin K. American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.3

<▼1><P><B>Background:</B> Resistance of ovarian cancer cells to chemotherapy is a major therapeutic problem.</P><P><B>Results:</B> Hirsutenone induces cisplatin sensitivity via p53, X-linked inhibitor of apoptosis protein, and apoptosis-inducing factor.</P><P><B>Conclusion:</B> Hirsutenone sensitizes resistant ovarian cancer cells to cisplatin.</P><P><B>Significance:</B> Co-treatment with hirsutenone may have the potential to overcome chemoresistance.</P></▼1><▼2><P>Cisplatin (CDDP) and its derivatives are considered first-line treatments for ovarian cancer (OVCA). However, despite initial results that often appear promising, in most cases patients will return with recurrent disease that fails to respond to further chemotherapy. We assayed a number of food phytochemicals with reported PI3K inhibitory ability to identify candidates that can influence CDDP treatment outcomes in chemoresistant OVCA cell lines. A direct comparison revealed that the diarylheptanoid hirsutenone from the tree bark of <I>Alnus hirsuta</I> var. sibirica was superior at inducing CDDP sensitivity in a number of chemoresistant cancer cell lines. Whereas hirsutenone treatment activated p53, its modest efficacy in <I>p53</I>-mutant and -null cell lines suggested the existence of a p53-independent mode of action. Further investigation revealed that hirsutenone causes CDDP-dependent apoptosis in chemoresistant cells by ubiquitin-proteasome-dependent X-linked inhibitor of apoptosis degradation and by enhancing the translocation of apoptosis-inducing factor from the mitochondria to the nucleus. This was found to be, at least in part, under the influence of upstream Akt activity, linking hirsutenone-dependent PI3K inhibition with downstream effects on apoptosis-inducing factor, X-linked inhibitor of apoptosis, and apoptosis. Our findings provide rationale for further investigation of the effects of hirsutenone on chemoresistant OVCA in clinical studies.</P></▼2>

Molecular determinants of ovarian cancer chemoresistance: new insights into an old conundrum

Ali, Ahmed Y.,Farrand, Lee,Kim, Ji Young,Byun, Sanguine,Suh, Jeong‐,Yong,Lee, Hyong Joo,Tsang, Benjamin K. Blackwell Publishing Inc 2012 Annals of the New York Academy of Sciences Vol.1271 No.1

<P>Ovarian cancer is the most lethal gynecological malignancy. Cisplatin and its derivatives are first-line chemotherapeutics, and their resistance is a major hurdle in successful ovarian cancer treatment. Understanding the molecular dysregulation underlying chemoresistance is important for enhancing therapeutic outcome. Here, we review two established pathways in cancer chemoresistance. p53 is a major tumor suppressor regulating proliferation and apoptosis, and its mutation is a frequent event in human malignancies. The PI3K/Akt axis is a key oncogenic pathway regulating survival and tumorigenesis by controlling several tumor suppressors, including p53. The interplay between these pathways is well established, although the oncogenic phosphatase PPM1D adds a new layer to this intricate relationship and provides new insights into the processes determining cell fate. Inhibition of the PI3K/Akt pathway by functional food compounds as an adjunct to chemotherapeutics may tip the balance in favor of apoptosis rather than survival, enhancing therapeutic efficacy, and reducing side effects.</P>

Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer

Lan Ying Li,김희정,박선애,이소현,김이경,이정윤,김성훈,김영태,김상운,남은지 대한암학회 2019 Cancer Research and Treatment Vol.51 No.3

Purpose Recurrence and chemoresistance (CR) are the leading causes of death in patients with highgrade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. Materials and Methods To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). Results Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLADPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845). Conclusion We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.

HIF-1α and GLUT1 Gene Expression is Associated with Chemoresistance of Acute Myeloid Leukemia

Song, Kui,Li, Min,Xu, Xiao-Jun,Xuan, Li,Huang, Gui-Nian,Song, Xiao-Ling,Liu, Qi-Fa Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.4

Aims: Much evidence suggests that increased glucose metabolism in tumor cells might contribute to the development of acquired chemoresistance. However, the molecular mechanisms are not fully clear. Therefore, we investigated a possible correlation of mRNA expression of HIF-$1{\alpha}$ and GLUT1 with chemoresistance in acute myeloid leukemia (AML). Methods: Bone marrow samples were obtained from newly diagnosed and relapsed AML (M3 exclusion) cases. RNA interference with short hairpin RNA (shRNA) was used to stably silence GLUT1 or HIF-$1{\alpha}$ gene expression in an AML cell line and HIF-$1{\alpha}$ and GLUT1 mRNA expression was measured by real-time quantitative polymerase chain reaction assay (qPCR). Results: High levels of HIF-$1{\alpha}$ and GLUT1 were associated with poor responsiveness to chemotherapy in AML. Down-regulation of the expression of GLUT1 by RNA interference obviously sensitized drug-resistant HL-60/ADR cells to adriamycin (ADR) in vitro, comparable with RNA interference for the HIF-$1{\alpha}$ gene. Conclusions: Our data revealed that over-expression of HIF-$1{\alpha}$ and GLUT1 might play a role in the chemoresistance of AML. GLUT1 might be a potential target to reverse such drug resistance.

Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells

JaeJin An,Eun-Mi Ha 한국미생물학회 2022 The journal of microbiology Vol.60 No.7

Metabolic abnormalities are one of the main hallmarks of cancer and are associated with chemoresistance. Therefore, targeting the metabolic reprogramming of cancer cells has the potential to overcome chemoresistance. Probiotic-derived extracellular vesicles (EVs) play important roles in biological function and intracellular communication. However, the inhibitory effect of Lactobacillus plantarum-derived EVs (LpEVs) on colorectal cancer (CRC) cells has not yet been elucidated. This study clearly revealed that increased glycolysis in 5-fluorouracil (5-FU)-resistant CRC cells (CRC/5FUR) is directly related to chemoresistance and that the metabolic shift reversed by LpEVs inhibits cancer cell proliferation and eventually leads to apoptosis. Pyruvate dehydrogenase kinase 2 (PDK2), one of the crucial enzymes for enhancing glycolysis, was upregulated in CRC/5FUR cells. In our study, LpEVs sensitized CRC/5FUR cells to 5-FU by attenuating PDK2 expression in p53-p21-dependent metabolic signaling, thereby circumventing 5-FU resistance. We demonstrated the effect of cellular responses to 5-FU by modifying the PDK2 expression level in both 5-FU-sensitive parental CRC and 5- FU resistant CRC cell lines. Finally, we revealed that the PDK2 signaling pathway can potentially be targeted using LpEVs treatment to overcome chemoresistant CRC, thereby providing a potential strategy for CRC treatment by intervening in tumor metabolism.

Association between Epstein-Barr Virus In-fection and Chemoresistance to Docetaxel in Gastric Carcinoma

Hee Jong Shin,김도년,이숙경 한국분자세포생물학회 2011 Molecules and cells Vol.32 No.2

Epstein-Barr virus (EBV) is associated with human can-cers such as nasopharyngeal carcinoma, Burkitt’s lym-phoma, Hodgkin’s disease, and gastric carcinoma (GC). EBV is associated with about 10% of all GC cases globally. EBV-associated GC has distinct features from EBV-ne-gative GC. However, it is still unclear if EBV infection has any effect on GC chemoresistance. Cell proliferation assay, cell cycle analysis, and active caspase Western blot revealed that the EBV-positive GC cell line (AGS-EBV) showed chemoresistance to docetaxel compared to the EBV-negative GC cell line (AGS). Docetaxel treatment increased expression of Bax similarly in AGS and AGS-EBV cell lines. However, Bcl-2 induction was markedly higher in AGS-EBV cells, after docetaxel treatment. Although docetaxel increased the expression of p53 to a similar extent in both cell lines, induction of p21 in AGS-EBV cells was lower than in AGS cells. Furthermore, expression of survivin was higher in AGS-EBV cells than in AGS cells following docetaxel treatment as well as at basal state. EBV-lytic gene expression was induced by docetaxel treatment in AGS-EBV cells. The results suggest that EBV infection and lytic induction confers chemoresistance to GC, possibly by regulating cellular and EBV latent and lytic gene ex-pression.

MEG3 LncRNA from Exosomes Released from Cancer-Associated Fibroblasts Enhances Cisplatin Chemoresistance in SCLC via a MiR-15a-5p/CCNE1 Axis

Yulu Sun,Guijun Hao,Mengqi Zhuang,Huijuan Lv,Chunhong Liu,Keli Su 연세대학교의과대학 2022 Yonsei medical journal Vol.63 No.3

Purpose: Long non-coding RNAs (lncRNAs) may act as oncogenes in small-cell lung cancer (SCLC). Exosomes containing lncRNAsreleased from cancer-associated fibroblasts (CAF) accelerate tumorigenesis and confer chemoresistance. This studyaimed to explore the action mechanism of the CAF-derived lncRNA maternally expressed gene 3 (MEG3) on cisplatin (DDP) chemoresistanceand cell processes in SCLC. Materials and Methods: Quantitative real-time PCR was conducted to determine the expression levels of MEG3, miR-15a-5p, andCCNE1. Cell viability and metastasis were measured by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-h-tetrazolium bromide andinvasion assays, respectively. A xenograft tumor model was developed to confirm the effect of MEG3 overexpression on SCLC progressionin vivo. Relationships between miR-15a-5p and MEG3/CCNE1 were predicted using StarBase software and validated bydual luciferase reporter assay. Western blotting was used to determine protein levels. A co-culture model was established to explorethe effects of exosomes on MEG3 expression in SCLC cell lines. Results: MEG3 was overexpressed in SCLC tissues and cells. MEG3 silencing significantly repressed cell viability and metastasis inSCLC. High expression of MEG3 was observed in CAF-derived conditioned medium (CM) and exosomes, and promoted chemoresistanceand cancer progression. Additionally, MEG3 was found to serve as a sponge of miR-15a-5p to mediate CCNE1 expression. Overexpression of miR-15a-5p and knockout of CCNE1 reversed the effects of MEG3 overexpression on cell viability and metastasis. Conclusion: MEG3 lncRNA released from CAF-derived exosomes promotes DDP chemoresistance via regulation of a miR-15a-5p/CCNE1 axis. These findings may provide insight into SCLC therapy.