Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis

Grimmig, Tanja; Moll, Eva-Maria; Kloos, Kerstin; Thumm, Rebecca; Moench, Romana; Callies, Simone; Kreckel, Jennifer; Vetterlein, Malte W.; Pelz, Joerg; Polat, Buelent; Tripathi, Sudipta; Rehder, Roberta; Ribas, Carmen Austrália Paredes Marcondes; Chandraker, Anil; Germer, C.-T.; Waaga-Gasser, Ana Maria; Gasser, Martin

doi:10.1177/1179064417730559

Cited by 30 publications

(23 citation statements)

References 52 publications

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“…Another possible reason for the absence of change in mot‐2 protein levels could be due to the nature of mot‐2 as a heat‐shock protein. While UBXN2A overexpression decreases mot‐2 protein levels through the ubiquitin–proteasome pathway, mot‐2 can be upregulated transcriptionally in response to genotoxic stress in colon cancer cells (Grimmig et al ., ; Swindell et al ., ) induced by 5‐FU treatment.…”

Section: Resultsmentioning

confidence: 98%

UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells

et al. 2018

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Overexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug‐induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin‐2 (mot‐2) is a dominant oncoprotein in several tumors, including colorectal cancer (CRC). In addition to inactivating the p53 tumor suppressor protein, mot‐2 enhances tumor cell invasion and migration. Thus, mot‐2 is considered a potential therapeutic target in several cancer types. The current study investigated the biological role of a ubiquitin‐like protein called UBXN2A in the regulation of mot‐2 turnover. An orthogonal ubiquitin transfer technology followed by immunoprecipitation, in vitro ubiquitination, and Magnetic Beads TUBE2 pull‐down experiments revealed that UBXN2A promotes carboxyl terminus of the HSP70‐interacting protein (CHIP)‐dependent ubiquitination of mot‐2. We subsequently showed that UBXN2A increases proteasomal degradation of mot‐2. A subcellular compartmentalization experiment revealed that induced UBXN2A decreases the level of mot‐2 and its chaperone partner, HSP60. Pharmacological upregulation of UBXN2A using a small molecule, veratridine (VTD), decreases the level of mot‐2 in cancer cells. Consistent with the in vitro results, UBXN2A+/− mice exhibited selective elevation of mot‐2 in colon tissues. An in vitro Anti‐K48 TUBE isolation approach showed that recombinant UBXN2A enhances proteasomal degradation of mot‐2 in mouse colon tissues. Finally, we observed enhanced association of CHIP with the UBXN2A‐mot‐2 complex in tumors in an azoxymethane/dextran sulfate sodium‐induced mouse CRC model. The existence of a multiprotein complex containing UBXN2A, CHIP, and mot‐2 suggests a synergistic tumor suppressor activity of UBXN2A and CHIP in mot‐2‐enriched tumors. This finding validates the UBXN2A‐CHIP axis as a novel and potential therapeutic target in CRC.

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Section: Resultsmentioning

confidence: 98%

UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells

et al. 2018

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“…Previous transcriptomic analysis focused on cellular models of cancer and the impact of hyperthermia (9). These studies serve to provide critical insights on the pathways activated by hyperthermia including heat shock proteins (21,37). Indeed, we observed activation of heat shock response pathways at the bulk RNAseq level.…”

Section: Discussionmentioning

confidence: 88%

“…Epithelial cells were localized in cluster 7 (Figure 2A-D, Supplemental Table 2) and showed no significant changes in cell density pre-and post-HIPEC ( Figure 3B). At the transcriptional level there were significant increases in heat-shock proteins, HSPA6, DNAJB1, CRYAB, and HSP90AB1 (21,22,37), in the HIPEC-treated specimen (Supplemental Table 7). HPA6, in particular, has been previously found to be upregulated in ovarian cancer cell lines treated with Magnetic Fluid Hyperthermia MFH, and its inhibition in vivo was successful in reducing tumor growth (38).…”

Section: Complement Pathwaysmentioning

confidence: 99%

Single-Cell Analysis of Hyperthermic Intraperitoneal Chemotherapy Treated Tumors Reveals Distinct Cellular and Molecular Responses

Horowitz¹,

Alali²,

Alban³

et al. 2020

Preprint

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SummaryHyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a clinical regimen that prolongs overall survival for patients with advanced Epithelial Ovarian Cancer (EOC). However, the mechanism of action of HIPEC remains poorly understood. To provide insights into the rapid changes that accompany HIPEC, tumors from five patients with high grade serous ovarian cancer were harvested from the omentum at time of debulking and after 90 minutes of HIPEC treatment. Specimens were rapidly dissociated into single cells and processed for single cell RNA-seq. Unbiased clustering identified 19 cell clusters that were annotated based on cellular transcriptome signatures to identify the epithelial, stromal, T and B immune cells, macrophages, and natural killer cell populations. Hallmark pathway analysis revealed heat shock, metabolic reprogramming, inflammatory, and EMT pathway enrichment in distinct cell populations upon HIPEC treatment. Collectively, our findings provide the foundation for mechanistic studies focused on how HIPEC orchestrates the ovarian cancer tissue response.

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“…13 Others have suggested increased heat shock protein expression may mediate resistance. 14 Investigators should be encouraged to pursue translational research as part of HIPEC procedures to better understand the immune and tumor microenvironment effects. This work would potentially provide new directions for novel therapeutic strategies.…”

mentioning

confidence: 99%

“…In colon cancer models, HIPEC induces dendritic cell activation mediated by heat shock proteins, which lead to T‐cell activation and an antitumor effect 13 . Others have suggested increased heat shock protein expression may mediate resistance 14 . Investigators should be encouraged to pursue translational research as part of HIPEC procedures to better understand the immune and tumor microenvironment effects.…”

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confidence: 99%

Intraperitoneal chemotherapy: Hot, timely, and relevant?

Mackay

Kohn

2020

Cancer

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Only 45% of women diagnosed with epithelial ovarian cancer (EOC) will remain alive 5 years after their diagnosis. 1 For several decades, we have seen little progress in terms of overall survival (OS). However, we have now entered a new era with increased knowledge of ovarian cancer biology, and this has led to new therapeutic options and an understanding that 1 size does not fit all for women diagnosed with this disease. 2 Our current challenge is how to interpret the emerging data to inform treatment decisions for the individual women that we see in the clinic. Nowhere is this more apparent than in the role of the combination of optimal cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). The use of HIPEC has been growing in popularity in recent years, although initially there were no randomized data to support its use. Even with a positive randomized trial, issues concerning the study design and the statistical analysis raise questions about whether HIPEC should be recommended as a standard-of-care approach. There are many questions that remain unanswered. They include the fundamental question of whether there is a role for intraperitoneal (IP) chemotherapy, hot or cold, as our use of targeted agents becomes more sophisticated. If there is a role for HIPEC, when should it be considered, and is hyperthermia necessary? Ultimately, we need to understand which women will derive a benefit from this approach or, perhaps more importantly, identify those who will not benefit. For implementing HIPEC, the real-world analyses provided by Ghirardi et al 3 are important because they can help us to understand patient selection and tolerability and help to guide physicians and women in making a choice. IP delivery of chemotherapy relies on the presumption that the cancer cells are inherently chemosensitive and that there is a dose-response relationship (ie, "more is better"). EOC lends itself to this approach because the residual disease after surgery and the initial recurrence are primarily confined to the abdominal cavity. Certain chemotherapeutic agents have a pharmacokinetic advantage with higher IP concentrations and a longer half-life of the drug in the peritoneal cavity in comparison with intravenous (IV) administration. For cisplatin, this translates into 10-to 20-fold greater exposure, and for other drugs such as paclitaxel, this ratio is even higher. 4 In 2006, the National Cancer Institute issued an alert after reviewing the data from 7 randomized clinical trials exploring the combination of serial cold IP and IV administration versus IV administration alone after optimal cytoreductive surgery for EOC. IP/IV chemotherapy was associated with a 21.6% decrease in the risk of death and an approximately 12-month increase in median OS. However, IP delivery also resulted in greater complexity, more toxicity, and significant resource implications. In addition, the design and statistical analysis of individual studies raised questions about the true benefit of this approach. IP/IV administration was ...

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Upregulated Heat Shock Proteins After Hyperthermic Chemotherapy Point to Induced Cell Survival Mechanisms in Affected Tumor Cells From Peritoneal Carcinomatosis

Cited by 30 publications

References 52 publications

UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells

UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells

Single-Cell Analysis of Hyperthermic Intraperitoneal Chemotherapy Treated Tumors Reveals Distinct Cellular and Molecular Responses

Intraperitoneal chemotherapy: Hot, timely, and relevant?

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