Spexin is a novel hormone involved in obesity and diabetes while its biofunctional significance in lipid metabolism is still to be comprehended. Global metabolomic analysis in the present study revealed multiple metabolic pathways altered by spexin intraperitoneal (i.p.) injection in rat serum, which are highlighted by the changes in several bile acid metabolites. In rats, spexin (300 μg/kg) could dramatically reduce hepatic and circulating total bile acids (TBA) level compared with the controls. Correspondingly, treatment with spexin by i.p. injection for 28 days led to significant decrease in serum TBA and gallbladder weight in C57BL/6J mice. In enterohepatic circulation system, spexin effectively reduced TBA levels in mouse liver and gallbladder but not the intestine. Hepatic cholesterol 7α-hydroxylase 1 (CYP7A1) expression, unsurprisingly, was suppressed by spexin injection. Both GALR2 and GALR3 antagonists reversed the inhibitory effects of spexin on concentrations of serum TBA and 7 α-hydroxy-4-cholesten-3-one (C4), and hepatic CYP7A1 expression. Finally, negative correlations were observed between serum spexin and total cholesterol (TC), total bile acid (TBA), tauro-chenodeoxycholate (TCDCA), as well as glycochenodeoxycholate (GCDCA) in 91 healthy volunteers. These findings illuminate the intrinsic importance of spexin in the regulation of bile acid synthesis and metabolism.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer with poor prognosis. Here, we present a peptide−drug conjugate (PDC)bradykinin-potentiating peptide-paclitaxel (BPP-PTX) conjugatesynthesized by conjugating BPP9a with PTX via a succinyl linker. BPP-PTX targets the angiotensin-converting enzyme (ACE) on TNBC cells. ACE was found to be ectopically expressed in two TNBC cell lines but was absent in both the receptor-positive breast cancer cell line and healthy kidney cell line. Overexpression, knockdown, and competitive inhibition experiments demonstrated ACE-mediated cytotoxicity of BPP-PTX. In vivo, ACE-positive tumors were enriched with BPP-PTX, with the PDC being better tolerated than plain PTX. Compared with plain PTX, BPP-PTX exhibited improved tumor-suppressive effects in MDA-MB-468 xenografted female nude mice. Meanwhile, BPP-PTX resulted in less body weight loss and white blood cell reduction toxicity. These results collectively imply the novelty, efficacy, and low-toxicity profile of BPP-PTX as a potential therapeutic for ACE-positive TNBC.

Lung cancer, claiming millions of lives annually, has the highest mortality rate worldwide. This advocates the development of novel cancer therapies that are highly toxic for cancer cells but negligibly toxic for healthy cells. One of the effective treatments is targeting overexpressed surface receptors of cancer cells with receptor-specific drugs. The receptors-in-focus in the current review are the G-protein coupled receptors (GPCRs), which are often overexpressed in various types of tumors. The peptide subfamily of GPCRs is the pivot of the current article owing to the high affinity and specificity to and of their cognate peptide ligands, and the proven efficacy of peptide-based therapeutics. The article summarizes various ectopically expressed peptide GPCRs in lung cancer, namely, Cholecystokinin-B/Gastrin receptor, the Bombesin receptor family, Bradykinin B1 and B2 receptors, Arginine vasopressin receptors 1a, 1b and 2, and the Somatostatin receptor type 2. The autocrine growth and pro-proliferative pathways they mediate, and the distinct tumor-inhibitory effects of somatostatin receptors are then discussed. The next section covers how these pathways may be influenced or ‘corrected’ through therapeutics (involving agonists and antagonists) targeting the overexpressed peptide GPCRs. The review proceeds on to Nano-scaled delivery platforms, which enclose chemotherapeutic agents and are decorated with peptide ligands on their external surface, as an effective means of targeting cancer cells. We conclude that targeting these overexpressed peptide GPCRs is potentially evolving as a highly promising form of lung cancer therapy.

No abstract

There is mounting evidence that interleukin-9 (IL-9) is associated with cancer although its function in lung cancer remains elusive. This study aimed to elucidate the role of IL-9 in lung cancer and the mechanisms involved. We report the detection of interleukin-9 receptor (IL-9R) expression in CMT167 cells, but not in Lewis lung carcinoma (LLC) cells. LLC or CMT167 cells were inoculated in wildtype C57BL/6J immunocompetent mice. Tumor-bearing mice were randomized on day 3 post-inoculation (8 mice per group) to receive intraperitoneal treatment with murine recombinant IL-9 (50 ng/mouse on alternate days) ± anti-programmed cell death protein 1 (anti-PD-1, 10 mg/kg, every three days) or control until reaching humane endpoints whereby tumors were harvested. In LLC tumor-bearing mice, neither tumor growth nor intratumoral T cells were affected by IL-9 treatment. Nonetheless IL-9 decreased CMT167 tumor growth and enhanced anti-tumor T cell responses, both of which were absent in IL-9R knockdown CMT167 tumors. CD8+ T cells were identified as the key effector driving IL-9-induced tumor suppression in the CMT167 model. Increased dendritic cell population and MHC-I expression were observed in IL-9-treated CMT167 tumors. Simultaneously, PD-1 and programmed death ligand 1 (PD-L1) expression by CD8+ T cells and CMT167 cells was upregulated. The combination of IL-9 and anti-PD-1 antibody synergistically suppressed CMT167 tumor and enhanced tumor-infiltrating proportion of CD8+ T cells. Taken together, our study determined the role of IL-9 in anti-tumor immunity and proposes IL-9 as a promising adjuvant to immune checkpoint blockade in lung cancer.