Bone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials.Here, we identified two separate and independent survival pathways induced by the bone tumor microenvironment that are hyperactivated in CRPC and confer resistance to PI3K inhibitors. The first pathway involves integrin α6β1-mediated adhesion to laminin and the second involves hypoxia-induced expression of PIM kinases. In vitro and in vivo models demonstrate that these pathways transduce parallel but independent signals that promote survival by reducing oxidative stress and preventing cell death. We further demonstrate that both pathways drive resistance to PI3K inhibitors in PTEN-negative tumors. These results provide preclinical evidence that combined inhibition of integrin α6β1 and PIM kinase in CRPC is required to overcome tumor microenvironment-mediated resistance to PI3K inhibitors in PTEN-negative tumors within the hypoxic and laminin-rich bone microenvironment.
Resistance to chemotherapy represents a major obstacle to the successful treatment of non-small cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intercellular ROS. Mechanistically, we define a signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1, causing marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC to chemotherapy and produced a synergistic anti-tumor response in vitro and in vivo.Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge about how PIM1 regulates mitochondria and provide justification for combining PIM inhibition with chemotherapy in NSCLC.
Resistance to chemotherapy represents a major obstacle to the successful 35 treatment of non-small cell lung cancer (NSCLC). The goal of this study was to determine 36 how PIM kinases impact mitochondrial dynamics, ROS production, and response to 37 chemotherapy in lung cancer. Live cell imaging and microscopy were used to determine 38 the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM 39 kinases caused excessive mitochondrial fission and significant upregulation of 40 mitochondrial superoxide, increasing intercellular ROS. Mechanistically, we define a 41 signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition 42 significantly increased the protein levels and mitochondrial localization of Drp1, causing 43 marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 44 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC to 45 chemotherapy and produced a synergistic anti-tumor response in vitro and in vivo.46 Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors 47 promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge 48 about how PIM1 regulates mitochondria and provide justification for combining PIM 49 inhibition with chemotherapy in NSCLC. 50 51 52 species 53 54 55Introduction: Lung cancer is the second most commonly diagnosed type of cancer and 56 the leading cause of cancer-related mortality worldwide. More than two-thirds of lung 57 cancer patients are diagnosed at an advance stage (III-IV), and intrinsic and/or acquired 58 resistance to treatment represent major obstacles to the successful treatment of patients 59 with advanced disease (1,2). As compared to other types of lung cancer, non-small cell 60 lung carcinomas (NSCLC) is less prone to undergo spontaneous and treatment-induced 61 apoptosis (3), suggesting that deficiencies in the apoptotic process may be responsible 62 for their and/or acquired resistance to chemotherapy (4). 63Cumulative evidence has demonstrated that an imbalance of mitochondrial fission 64 and fusion is common in cancer (5). Mitochondria exist as a dynamic network that is 65 constantly undergoing fusion (elongation) and fission (fragmentation). Mitochondrial 66 fusion results in a tubular mitochondrial network that serves to counteract metabolic 67 insults, maintain cellular integrity, and provide protection against cell death (6,7). In 68 contrast, mitochondrial fission creates small and fragmented mitochondria, which can 69 have both pro-and anti-tumor effects depending on the cellular context (8). Mitochondrial 70 fission is required for cell division and has been shown to positively regulate cell 71 proliferation in cancer cells (9). However, in response to apoptotic stimuli and cellular 72 stress, too much fission generates excessive reactive oxygen species (ROS) and is a 73 necessary event for the initiation of apoptosis (10). Mitochondrial fusion is associated with 74 chemoresistance in seve...
Angiogenesis is essential for the sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Therefore, understanding the mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis. Herein, we establish a new regulatory mechanism responsible for the constitutive activation of HIF-1α in cancer, irrespective of oxygen tension. PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits. In vitro and in vivo models demonstrate that expression of PIM1 is sufficient to stabilize HIF-1α and HIF-2α in normoxia and stimulate angiogenesis in a HIF-1-dependent manner. CRISPR mutants of HIF-1α (Thr455D) promoted increased tumor growth, proliferation and angiogenesis. Moreover, HIF-1α-T455D xenograft tumors were refractory to the anti-angiogenic and cytotoxic effects of PIM inhibitors. These data identify a new signaling axis responsible for hypoxia-independent activation of HIF-1 and expand our understanding of the tumorigenic role of PIM1 in solid tumors.
Distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway linking hypoxia and PIM1 kinase to the actin cytoskeleton and cell motility. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the wave regulatory complex (WRC), as a PIM1 substrate. Phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels and enhanced WRC formation, resulting in increased protrusive activity and cell motility. Cell protrusion induced by hypoxia and/or PIM1 was dependent on ABI2. In vivo smooth muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion, and treatment with PIM inhibitors significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.