The neurotransmitter acetylcholine (ACh) acts as an autocrine growth factor for human lung cancer. Several lines of evidence show that lung cancer cells express all of the proteins required for the uptake of choline (choline transporter 1, choline transporter-like proteins) synthesis of ACh (choline acetyltransferase, carnitine acetyltransferase), transport of ACh (vesicular acetylcholine transport, OCTs, OCTNs) and degradation of ACh (acetylcholinesterase, butyrylcholinesterase). The released ACh binds back to nicotinic (nAChRs) and muscarinic receptors on lung cancer cells to accelerate their proliferation, migration and invasion. Out of all components of the cholinergic pathway, the nAChR-signaling has been studied the most intensely. The reason for this trend is due to genome-wide data studies showing that nicotinic receptor subtypes are involved in lung cancer risk, the relationship between cigarette smoke and lung cancer risk as well as the rising popularity of electronic cigarettes considered by many as a "safe" alternative to smoking. There are a small number of review articles which review the contribution of the other cholinergic proteins in the pathophysiology of lung cancer. The primary objective of this review article is to discuss the function of the acetylcholine-signaling proteins in the progression of lung cancer. The investigation of the role of cholinergic network in lung cancer will pave the way to novel molecular targets and drugs in this lethal malignancy.

The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound antineoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation. This has led to extensive research focused on the identification and rational design of second-generation capsaicin analogs, which possess greater bioactivity than capsaicin. A majority of these natural capsaicinoids and synthetic capsaicin analogs have been studied for their pain-relieving activity. Only a few of these capsaicin analogs have been investigated for their anticancer activity in cell culture and animal models. The present review summarizes the current knowledge of the growth-inhibitory activity of natural capsaicinoids and synthetic capsaicin analogs. Future studies that examine the anticancer activity of a greater number of capsaicin analogs represent novel strategies in the treatment of human cancers.

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The nutritional compound capsaicin inhibits the invasion of many types of human cancers. The clinical development of capsaicin as an anti-cancer drug is limited due to its unfavorable side effects like burning sensation, stomach cramps, gut pain and nausea. This study compared the anti-invasive activity of capsaicin to non-pungent long chain capsaicin analogs, namely arvanil and olvanil, in human small cell lung cancer cells. Boyden chamber invasion assays revealed that arvanil and olvanil displayed improved anti-invasive activity relative to capsaicin in human SCLC cells. The results of the Boyden chamber assay were confirmed by the spherical invasion assay, and similar results were obtained. The anti-invasive activity of arvanil, olvanil and capsaicin were independent of TRPV and CB1 receptors. Furthermore, the anti-invasive activity of arvanil, olvanil and capsaicin was mediated by the AMPK pathway. Depletion of AMPK levels by siRNA methodology abrogated the anti-invasive activity of arvanil, olvanil and capsaicin. The non-pungent capsaicin analogs arvanil and olvanil display improved anti-invasive activity relative to capsaicin in human SCLC cells. These agents may represent the second generation of capsaicin-like compounds which are more potent than the parent molecule and have a better side effect profile.

Small cell lung cancer (SCLC) is characterized by excellent initial response to chemotherapy and radiation therapy with a majority of the patients showing tumor shrinkage and even remission. However, the challenge with SCLC therapy is that patients inevitably relapse and subsequently do not respond to the first line treatment. Recent clinical studies have investigated the possibility of camptothecin-based combination therapy as first line treatment for SCLC patients. Conventionally, camptothecin is used for recurrent SCLC and has poor survival outcomes. Therefore, drugs which can improve the therapeutic index of camptothecin should be valuable for SCLC therapy. Extensive evidence shows that nutritional compounds like capsaicin (the spicy compound of chili peppers) can improve the anti-cancer activity of chemotherapeutic drugs in both cell lines and animal models. Statistical analysis shows that capsaicin synergizes with camptothecin to enhance apoptosis of human SCLC cells. The synergistic activity of camptothecin and capsaicin is observed in both classical and variant SCLC cell lines and, in vivo, in human SCLC tumors xenotransplanted on chicken chorioallantoic membrane (CAM) models. The synergistic activity of capsaicin and camptothecin are mediated by elevation of intracellular calcium and the calpain pathway. Our data fosters hope for novel nutrition based combination therapies in SCLC.

Aneuploid mucinous colorectal adenocarcinoma (MAC) is an aggressive subtype of colorectal cancer with poor prognosis. The tumorigenic mechanisms in aneuploid MAC are currently unknown. Here we show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of MAC. Loss of FILIP1L increased xenograft growth, and, in colon-specific knockout mice, induced colonic epithelial hyperplasia and mucin secretion. The molecular chaperone prefoldin 1 (PFDN1) was identified as a novel binding partner of FILIP1L at the centrosomes throughout mitosis. FILIP1L was required for proper centrosomal localization of PFDN1 and regulated proteasome-dependent degradation of PFDN1. Importantly, increased PFDN1, caused by downregulation of FILIP1L, drove multi-nucleation and cytokinesis defects in vitro and in vivo, which were confirmed by time-lapse imaging and 3D cultures of normal epithelial cells. Overall, these findings suggest that downregulation of FILIP1L and subsequent upregulation of PFDN1 is a driver of the unique neoplastic characteristics in aggressive aneuploid MAC. STATEMENT OF SIGNIFICANCEThis study identifies FILIP1L as a tumor suppressor in mucinous colon cancer and demonstrates that FILIP1L loss results in aberrant stabilization of a centrosome-associated chaperone protein to drive aneuploidy and disease progression.Approximately half of MAC tumors are aneuploid (3-7), whereas the remainder are diploid and associated with microsatellite instability. Aneuploid MAC tumors were shown to be clinically more aggressive than diploid tumors (8,9). Compared to common colorectal adenocarcinoma, MAC has an entirely different molecular "signature", as well as an aberrant and aggressive metastatic pattern that is associated with poor response to treatment and worse prognosis (2). The mechanisms of MAC tumorigenesis are currently unknown.Filamin A interacting protein 1-like (FILIP1L) is a tumor suppressor that we identified in several types of cancer, including CRC (10-13). We showed that FILIP1L expression is down-regulated by promoter methylation (10, 12), a key mechanism of tumor suppressor down-regulation in cancer. Down-regulation of FILIP1L is associated with chemo-resistance and worse prognosis in ovarian and colon cancer (14,15). Moreover, its expression is inversely correlated with the invasive/aggressive potential of tumors and with epithelial-to-mesenchymal (EMT) marker expression (11,16). Its structural homologies and centrosomal localization suggest that FILIP1L may bind to elements of the cytoskeleton, and chaperone proteins to proteasomes (11,17,18).The prefoldin1 (PFDN1) chaperone is overexpressed in multiple cancer types and is associated with poor prognosis in colon cancer (19,20). PFDN1 participates in a multimeric prefoldin complex that facilitates proper folding of key cytoskeletal components such as actin and tubulins.Loss of PFDN1 decreases tubulin levels, thereby reducing microtubule growth and causing defects in cell division and embryonic lethality (21), though the mechanisms are unkno...

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The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound anti‐neoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps and burning sensation. This has led to extensive research focused on the identification and rational design of second‐generation capsaicin analogs. Previous studies have shown that addition of long‐chain unsaturated groups after the amide group of capsaicin were non‐pungent and retained the bioactivity of capsaicin. The chemical nature of these compounds are unsaturated N‐acylvanillamides (uN‐AVAMs). However, a majority of these uN‐AVAMs have been studied for their pain‐relieving activity. We synthesized a panel of uN‐AVAMs with 0–4 double bonds in the side chain of capsaicin. We investigated the growth‐inhibitory activity of these compounds with an MTT‐based screening assay. We selected our “hit compound” Arvanil for further studies. Next, we compared the apoptotic activity of arvanil and capsaicin in a panel of human small cell lung cancer (SCLC) cells. We observed that the non‐pungent capsaicin‐analog arvanil displayed greater magnitude of apoptosis than capsaicin. The pro‐apoptotic activity of arvanil and capsaicin was mediated by the intracellular calcium pathway. We measured the uN‐AVAM‐induced levels of intracellular calcium in SCLC cells. The pattern of uN‐AVAM‐induced intracellular calcium was analogous to the results obtained in the MTT assay. Therefore, the measurement of intracellular calcium may be used as a screening tool for capsaicin‐mimetics with anti‐cancer activity.Support or Funding InformationFunding for our study was supported by a NIH R15‐AREA Grant (2R15CA161491‐02). Furthermore, this study was supported in part by an Institutional Development Award (IDeA) Grant number P20GM104932 from the National Institute of General Medical Sciences (NIGMS) and the Research Core B of COBRE, a component of the National Institutes of Health (NIH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.