Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2

Wang, Dongliang; Zhao, Chaoshuai; Xu, Fei; Zhang, Aimi; Jin, Mingming; Zhang, Kunchi; Liu, Liu; Hua, Qian; Zhao, Jian; Li, Jianjun; Yang, Hao; Huang, Gang

doi:10.7150/thno.51797

Cited by 135 publications

(99 citation statements)

References 47 publications

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“…PKM2 is a key enzyme involved in glycolysis regulation and has an important regulatory role in cancer progression/resistance under hypoxia conditions (23)(24)(25)(26). It has been reported that exosomal PKM2 secreted by hypoxic cisplatin-resistance cells transmitted cisplatin-resistance to sensitive non-small cell lung cancer (NSCLC) cells both in vitro and in vivo (27). In present study, we found that hypoxia/exos derived from A549 cells could signi cantly elevated PKM2 expression.…”

Section: Discussionsupporting

confidence: 45%

Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via AMPK/p38 To Promote Lung Cancer Progression

Zhou

Lan

et al. 2021

Preprint

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Background Hypoxia is a major regulator of tumor aggressiveness and metastasis in cancer progression. Exosomes (exos) play an important role in the communication between lung cancer and hypoxic microenvironment. However, the underlying mechanisms are largely undefined. Methods Exos isolated from A549 cells under hypoxia conditions. Transmission electron microscopy and nanoparticle tracking analysis were carried out to characterize exos. CCK-8 assay, flow cytometry, Western blot, wound healing and transwell assays were performed to assess the proliferation, apoptosis, migration, and invasion of A549 cells, respectively. The M2 polarization of macrophages was evaluated by RT-qPCR and Western blot analysis. In vivo nude mice model was established to determine the regulatory effect of hypoxia/exos on the progression of lung cancer. Results Hypoxic A549 cell-derived exos (hypoxia/exos) promoted the proliferation and migration, and inhibited the apoptosis in A549 cells. The expression of PKM2 was significantly upregulated in hypoxia/exos. Hypoxic exosomal PKM2 induced M2 polarization of macrophages by activating AMPK/p38 pathway. Co-culture with hypoxia/exos-treated macrophages enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) in A549 cells. Moreover, treatment with hypoxia/exos facilitated the tumor growth and lung metastasis of A549 cells. Conclusions Our findings reveal that hypoxic exosomal PKM2 induces M2 macrophage polarization via AMPK/p38 pathway, and thus exerts a simulative effect on the growth and metastasis of lung carcinoma.

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Section: Discussionsupporting

confidence: 45%

Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via AMPK/p38 To Promote Lung Cancer Progression

Zhou

Lan

et al. 2021

Preprint

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“…Increasing evidence demonstrate the therapeutic potential of targeting PKM2 in cancer and enhancing CP sensitivity [133][134][135][136]. Exosomal transfer of PKM2 in hypoxic condition results in the generation of reductive metabolites that counter CP-mediated ROS production, preventing apoptosis and DNA damage and providing condition for CP resistance [137].…”

Section: Cisplatin Resistancementioning

confidence: 99%

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

et al. 2021

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The failure of chemotherapy is a major challenge nowadays, and in order to ensure effective treatment of cancer patients, it is of great importance to reveal the molecular pathways and mechanisms involved in chemoresistance. Cisplatin (CP) is a platinum-containing drug with anti-tumor activity against different cancers in both pre-clinical and clinical studies. However, drug resistance has restricted its potential in the treatment of cancer patients. CP can promote levels of free radicals, particularly reactive oxygen species (ROS) to induce cell death. Due to the double-edged sword role of ROS in cancer as a pro-survival or pro-death mechanism, ROS can result in CP resistance. In the present review, association of ROS with CP sensitivity/resistance is discussed, and in particular, how molecular pathways, both upstream and downstream targets, can affect the response of cancer cells to CP chemotherapy. Furthermore, anti-tumor compounds, such as curcumin, emodin, chloroquine that regulate ROS and related molecular pathways in increasing CP sensitivity are described. Nanoparticles can provide co-delivery of CP with anti-tumor agents and by mediating photodynamic therapy, and induce ROS overgeneration to trigger CP sensitivity. Genetic tools, such as small interfering RNA (siRNA) can down-regulate molecular pathways such as HIF-1α and Nrf2 to promote ROS levels, leading to CP sensitivity. Considering the relationship between ROS and CP chemotherapy, and translating these findings to clinic can pave the way for effective treatment of cancer patients.

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“…Hypoxia exacerbated the drug resistance in lung cancer cells owing to upregulated expression of pyruvate kinase isozymes M2 (PKM2), which was observed in exosomes expressed by hypoxic cisplatin-resistance cells. Mechanisms associated with this process include enhanced glycolysis in NSCLC cells to generate reductive metabolites which neutralize cisplatin-induced reactive oxygen species (ROS), inhibition of apoptosis by exosomal PKM2 via a PKM2-BCL2-dependent manner, and reprogramming of CAFs to produce an acidic microenvironment that promotes NSCLC cell proliferation and cisplatin resistance [ 93 ].…”

Section: Clinical Applicationsmentioning

confidence: 99%

The role of exosomes in lung cancer metastasis and clinical applications: an updated review

et al. 2021

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Lung cancer is the leading cause of cancer-associated deaths accounting for 24% of all cancer deaths. As a crucial phase of tumor progression, lung cancer metastasis is linked to over 70% of these mortalities. In recent years, exosomes have received increasing research attention in their role in the induction of carcinogenesis and metastasis in the lung. In this review, recent studies on the contribution of exosomes to lung cancer metastasis are discussed, particularly highlighting the role of lung tumor-derived exosomes in immune system evasion, epithelial-mesenchymal transition, and angiogenesis, and their involvement at both the pre-metastatic and metastatic phases. The clinical application of exosomes as therapeutic drug carriers, their role in antitumor drug resistance, and their utility as predictive biomarkers in diagnosis and prognosis are also presented. The metastatic activity, a complex multistep process of cancer cell invasion, survival in blood vessels, attachment and subsequent colonization of the host's organs, is integrated with exosomal effects. Exosomes act as functional mediating factors in cell–cell communication, influencing various steps of the metastatic cascade. To this end, lung cancer cell-derived exosomes enhance cell proliferation, angiogenesis, and metastasis, regulate drug resistance, and antitumor immune activities during lung carcinogenesis, and are currently being explored as an important component in liquid biopsy assessment for diagnosing lung cancer. These nano-sized extracellular vesicles are also being explored as delivery vehicles for therapeutic molecules owing to their unique properties of biocompatibility, circulatory stability, decreased toxicity, and tumor specificity. The current knowledge of the role of exosomes highlights an array of exosome-dependent pathways and cargoes that are ripe for exploiting therapeutic targets to treat lung cancer metastasis, and for predictive value assessment in diagnosis, prognosis, and anti-tumor drug resistance.

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Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2

Cited by 135 publications

References 47 publications

Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via AMPK/p38 To Promote Lung Cancer Progression

Hypoxic Tumor-Derived Exosomes Induce M2 Macrophage Polarization via AMPK/p38 To Promote Lung Cancer Progression

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

The role of exosomes in lung cancer metastasis and clinical applications: an updated review

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