Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

Zhou, Wei; Sun, Wei; Yung, Mingo M. H.; Dai, Sheng; Cai, Yihua; Chen, Chi‐Wei; Meng, Yunxiao; Lee, Jennifer B.; Braisted, John C.; Xu, Yi; Southall, Noel; Shinn, Paul; Huang, Xuefeng; Song, Zhangfa; Chen, Xiulei; Kai, Yan; Cai, Xin; Li, Zongzhu; Hao, Qiang; Cheung, Annie N.Y.; Ngan, Hextan Y.S.; Liu, Stephanie S.; Barak, Stephanie; Hao, Jing; Dai, Zhijun; Tzatsos, Alexandros; Peng, Weiqun; Pei, Huadong; Han, Zhiyong; Chan, David W.; Wen-ling, Zheng; Zhu, Wenge

doi:10.1038/s41388-018-0238-8

Cited by 36 publications

(43 citation statements)

References 41 publications

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“…1-4 to ovarian cancer cell lines generated to become cisplatin resistant 47 to mimic human ovarian cancer that does not respond to cisplatin chemotherapy. The IGROV-1 CR and SKOV3 CR cell lines have cisplatin IC50s increased about fivefold that of their parent cell lines (IGROV-1 CR = 1.50 uM, SKOV3 CR = 10.4 uM) 47 . These cell lines exhibited different levels of HDAC1, HDAC2, and HDAC6 proteins (Fig.…”

Section: Combination Of Nexta and Aza In Cisplatin-resistant Cell Linmentioning

confidence: 99%

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

Moufarrij

Srivastava

Gomez

et al. 2020

Sci Rep

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Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53−/− ovarian cancer with HDAC6i/ DnMti led to an increase in tumor-killing cells such as ifng+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1 hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment. The five-year survival for ovarian cancer has remained unchanged for decades, and novel therapies are urgently needed 1. Ovarian cancer has the deadliest outcome among gynecologic cancers due to its late (typically Stage III or IV) presentation and aggressive phenotype. High-grade serous ovarian cancer, the most common subtype, is characterized by genomic instability with >95% of cases exhibiting mutations in the tumor suppressor P53 2. Treatment involves surgical staging and optimal debulking to reduce tumor burden, followed by chemotherapy with a platinum-based agent and a taxane, or vice versa (chemotherapy before surgery). Unfortunately most cancers recur within two years of chemotherapy. Significant advances in the pathobiology of the disease, including the identification of a subset of tumors with defects in homologous recombination (HR), have led to the use of PARP inhibitors, which can cause synthetic lethality in HR-deficient tumors. However, less than half of ovarian cancers are HR-deficient and there is no curative therapy for the majority of ovarian cancer patients 1,3. Cancer cells may be recognized as foreign by host immune cells that kill the cancer cells, but as they progress cancers exhibit mechanisms of immune evasion or immunoediting 4. The tumor microenvironment (TME) is composed of both pro-and anti-cancer immune cells. These include CD8 effector T cells that recognize specific antigens on tumor cells to kill them, natural killer (NK) cells, part of the innate immune system that can kill tumor cells, and immuno-suppressive cell types including macrophages, regulatory T cells, and myeloid-derived suppressor cells. Novel drugs that activate CD8 effector T cells to fight cancer cells, includ...

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Section: Combination Of Nexta and Aza In Cisplatin-resistant Cell Linmentioning

confidence: 99%

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

Moufarrij

Srivastava

Gomez

et al. 2020

Sci Rep

Self Cite

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“…According to the article previously reported, cytokines, particularly those related to cell proliferation, migration, invasion, immune response, and tumor microenvironment, could partially explain the tolerance of tumor cells to chemotherapeutic drugs [9,23,25,26]. Therefore, we selected and cultured two 5-Fu-resistant CRC cell lines (DLD-1 5-FuR and HCT116 5-FuR), and confirmed that there are certain cytokines related to CRC cell resistance by exchanging the culture medium of drug-resistant and non-resistant cell lines.…”

Section: Discussionmentioning

confidence: 99%

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

et al. 2020

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Purpose5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu.Materials and MethodsCXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells.ResultsIn this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13.ConclusionThese results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatment strategies.

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“…On the other hand, the increased ROS level in cancer cells might accelerates the development of tumor aggressiveness and drug resistance (Kumar et al, 2008). Increased ROS can activate cellular survival pathways including c-Myc-miR-137-EZH2 pathway , IL-11-JAK2-STAT5 pathway (Zhou et al, 2018), ATR-Chk1 pathway (Meng et al, 2018) and AXL (Oien et al, 2017) et al ROS may also mediate metabolism reprogramming (Cruz-Bermudez et al, 2019).…”

Section: Hypoxiamentioning

confidence: 99%

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

et al. 2020

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Platinum-based anticancer drugs, including cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin, are heavily applied in chemotherapy regimens. However, the intrinsic or acquired resistance severely limit the clinical application of platinum-based treatment. The underlying mechanisms are incredibly complicated. Multiple transporters participate in the active transport of platinum-based antitumor agents, and the altered expression level, localization, or activity may severely decrease the cellular platinum accumulation. Detoxification components, which are commonly increasing in resistant tumor cells, can efficiently bind to platinum agents and prevent the formation of platinum-DNA adducts, but the adducts production is the determinant step for the cytotoxicity of platinum-based antitumor agents. Even if adequate adducts have formed, tumor cells still manage to survive through increased DNA repair processes or elevated apoptosis threshold. In addition, autophagy has a profound influence on platinum resistance. This review summarizes the critical participators of platinum resistance mechanisms mentioned above and highlights the most potential therapeutic targets or predicted markers. With a deeper understanding of the underlying resistance mechanisms, new solutions would be produced to extend the clinical application of platinum-based antitumor agents largely.

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Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

Cited by 36 publications

References 41 publications

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

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