Aberrant expression of TMEM205 signaling promotes platinum resistance in ovarian cancer: An implication for the antitumor potential of DAP compound

Calo, Corinne; Smith, Brentley Q.; Dorayappan, Kalpana Deepa Priya; Saini, Uksha; Lightfoot, Michelle D.S.; Wagner, Vincent; Kalaiyarasan, Deepika; Cosgrove, Casey; Wang, Qi-En; Maxwell, G. Larry; Kálai, Tamás; Kuppusamy, Periannan; Cohn, David E.; Selvendiran, Karuppaiyah

doi:10.1016/j.ygyno.2021.10.076

Cited by 9 publications

(5 citation statements)

References 53 publications

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“…To explore the impact of inhibiting HFD-mediated EVs secretion and the modulation of oncogenic proteins in adipose and uterine tissues, our study employed a small molecule inhibitor targeting EVs regulatory pathway proteins (STAT3, STAT5, and TMEM205) [21][22][23], along with Metformin to inhibit EV secretion, the administration of HO-3867 and Metformin showed a notable trend towards reduced body weights and adipose tissue accumulations. However, the differences observed in the combined treatment of the high-fat diet (HFD) mice group did not reach statistical signi cance.…”

Section: Resultsmentioning

confidence: 99%

Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

Selvendiran,

Sakaue,

Zingarelli

et al. 2024

Preprint

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Endometrial cancer (EC) is the leading gynecologic malignancy in the United States with obesity implicated in 57% of cases. This research delves into the molecular complexities of extracellular vesicle (EV) secretion as carriers of oncogenic protein expression and their involvement in obesity-mediated EC. An understanding of these mechanisms is pivotal for unraveling pathways relevant to obesity-associated EC, thereby guiding the development of innovative prevention and treatment strategies. Our investigation revealed a significant increase in EV secretion carrying oncogenic proteins (TMEM205, STAT5, and FAS) in adipose and uterine tissues/serum samples from obese EC patients compared to their non-obese counterparts. We identified alterations in EV-regulating proteins (Rab7, Rab11, and Rab27a) in obesity-mediated EC patient adipose and uterine samples. Through a 24-week analysis of the effects of a 45% kcal high-fat diet (HFD) on mice, we observed heightened body weight, increased adipose tissue, enlarged uterine horns, and heightened inflammation in the HFD group. This correlated with elevated levels of EV secretion and increased expression of oncogenic proteins TMEM205, FAS, and STAT5, while the tumor suppressor gene PIAS3 was downregulated in adipose and uterine tissues in HFD treated mice. Furthermore, our study confirmed that adipocyte derived EVs increased EC cell proliferation and migration. Additionally, we identified that the small molecule inhibitors (HO-3867) or Metformin inhibited EV secretion in vitro and in vivo, demonstrating significant inhibition of high glucose or adipocyte-mediated EC cell proliferation and a reduction in body weight and adipose tissue accumulation when administered to HFD mice. Moreover, HO-3867 or Metformin treatment inhibits HFD induced hyperplasia by altered the expression of EV-regulated proteins (Rab7, Rab11, and Rab27a) and decreased oncogenic protein expression (TMEM205, FAS and STAT5) levels. This study provides critical insights into the mechanisms supporting obesity-mediated EV secretion with oncogenic protein expression, shedding light on their role in EC pathogenesis. Additionally, it offers pre-clinical evidence supporting the initiation of novel studies for EV-targeted therapies aimed at preventing obesity-mediated EC.

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Section: Resultsmentioning

confidence: 99%

Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

Selvendiran,

Sakaue,

Zingarelli

et al. 2024

Preprint

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“…TMEM205 regulates chemo-resistant associated proteins like exosome-regulatory proteins Rab11 and contributes resistance via increased exosomal efflux of intracellular platinum. Furthermore, they found TMEM205 inhibitors, L-2663, reduced exosome secretion, inhibited exosomal platinum efflux, and re-sensitized to platinum in resistant cells 47 .…”

Section: Exosome-mediated Chemotherapy Resistance In Ovarian Cancermentioning

confidence: 98%

The Roles of Exosomes in Ovarian Cancer Chemo-resistance

Liu¹,

Xiao²,

Zhang³

et al. 2023

J. Cancer

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As common gynecological oncology, ovarian cancer has a high fatality rate and poor overall survival, mainly because of nonspecific symptoms in the early stages and chemotherapy resistance. Exosomes, nano-sized vesicles secreted by almost all types of cells, carry valuable commodities such as proteins, lipids, enzymes, mRNAs, and miRNAs between cells. They take part in remodeling the tumor microenvironment, promoting tumor angiogenesis and metastasis, and regulating immune metastasis and chemotherapy resistance in ovarian cancer. Previous studies have reported that exosomes could transfer chemotherapy resistance from drug-resistant tumor cells to sensitive ones by delivering proteins and miRNAs. Also, exosomes are involved in chemotherapy resistance by transferring multidrug-resistancerelated transporters, decreasing apoptosis, promoting epithelial-to-mesenchymal transition, and changing signal transduction pathways. Furthermore, they play a significant role in early detection, chemotherapy efficacy evaluation, and treatment of ovarian cancer. Exosomes are applied as chemotherapeutic delivery vehicles and therapeutic targets to inhibit anti-tumor immune responses. In addition, exosomes can be developed for cancer immunotherapy because of their immunomodulatory potential. Therefore, the article reviews the latest research progress of exosomes in ovarian cancer to elaborate on the mechanisms of exosome-mediated chemotherapy resistance in ovarian cancer patients and provide a forecast on their clinical therapeutic potential in improving chemotherapy sensitivity.

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“…In platinum-resistant OC cell lines, TMEM205 transmembrane protein expression is 10-20 times higher, which may contribute to OC through exosome-mediated platinum drug efflux [44]. Exosomal CLPTM1L from a cisplatin-resistant OC cell line is capable of conferring cisplatin resistance in a drug-sensitive OC cell line [45].…”

Section: Exosomes Derived From Cellsmentioning

confidence: 99%

Advances in Exosomes as Diagnostic and Therapeutic Biomarkers for Gynaecological Malignancies

Miao

Zhu

et al. 2022

Cancers

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Background: Exosomes are extracellular vesicles that can be released by practically all types of cells. They have a diameter of 30–150 nm. Exosomes control the exchange of materials and information between cells. This function is based on its special cargo-carrying and transporting functions, which can load a variety of useful components and guarantee their preservation. Recently, exosomes have been confirmed to play a significant role in the pathogenesis, diagnosis, treatment, and prognosis of gynaecological malignancies. Particularly, participation in liquid biopsy was studied extensively in gynaecological cancer, which holds the advantages of noninvasiveness and individualization. Literature Review: This article reviews the latest research progress of exosomes in gynaecological malignancies and discusses the involvement of humoral and cell-derived exosomes in the pathogenesis, progression, metastasis, drug resistance and treatment of ovarian cancer, cervical cancer, and endometrial cancer. Advances in the clinical application of exosomes in diagnostic technology, drug delivery, and overcoming tumour resistance are also presented. Conclusion: Exosomes are potentially diagnostic and prognostic biomarkers in gynaecological malignancies, and also provide new directions for the treatment of gynaecological tumours, showing great clinical potential.

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Aberrant expression of TMEM205 signaling promotes platinum resistance in ovarian cancer: An implication for the antitumor potential of DAP compound

Cited by 9 publications

References 53 publications

Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

The Roles of Exosomes in Ovarian Cancer Chemo-resistance

Advances in Exosomes as Diagnostic and Therapeutic Biomarkers for Gynaecological Malignancies

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