A carbazole alkaloid deactivates mTOR through the suppression of rictor and that induces apoptosis in lung cancer cells

Abstract

Non-small cell lung cancer (NSCLC) is known to be a difficult cancer to treat because of its poor prognosis, limited option for surgery, and resistance to chemo or radiotherapy. In this study, we have demonstrated that suppression of rictor expression in A549 and H1299 NSCLC cells by mahanine, a carbazole alkaloid, disrupted constitutive activation of mTOR and Akt. Mahanine suppression of rictor gene expression and consequent attenuation of its protein expression affected the inhibition of mTOR (Ser-2481) and Akt (Ser-473) phosphorylation. Since mahanine treatment revealed this new insight of rictor-mTOR relationship, we examined an association between mTOR activation with rictor expression. Interestingly, in rictor knockdown (KD) NSCLC cells, mTOR activation was significantly impaired. Transfection of rictor over-expression vector into the NSCLC cells reversed this situation. In fact, both rictor KD and mahanine treated cells showed considerably depleted phospho-mTOR level. These results indicate that rictor is required to maintain constitutive activation of mTOR in lung cancer cells. When mTOR kinase activity in rictor KD cells was examined with Akt as substrate, a significant reduction of Akt phosphorylation indicated impairment of mTOR kinase potentiality. Disruption of mTOR and Akt activation caused drastic mortality of NSCLC cancer cells through apoptosis. Hence, our study reveals a new dimension in mTOR-rictor relationship, where rictor stands to be a suitable therapeutic target for lung cancer.

Medicinal Profile, Phytochemistry, and Pharmacological Activities of Murraya koenigii and its Primary Bioactive Compounds

“…These results established the potential of M. koenigii as an anticancer agent in vitro [11]. Additional evidence for the anticancer activity of M. koenigii has been obtained from rodent cancer cell lines, as well as different in vivo cancer models [12][13][14][22][23][24]114,115]. In an early study, histopathological evidence showed that M. koenigii extract treatment generated a decline in neoplasms in the colon [85].…”

“…The bark is helpful in treating snakebites [17][18][19][20]. The essential oil extracted from M. koenigii leaves is reported to possess anti-oxidative, hepatoprotective [21][22][23][24], antimicrobial, antifungal [25][26][27], anti-inflammatory, and nephroprotective activities in animal models [28][29][30]. The medicinal properties of M. koenigii have been accredited to several chemical constituents of different carbazole alkaloids and other important metabolites, like terpenoids, flavonoids, phenolics, carbohydrates, carotenoids, vitamins, and nicotinic acid from different parts of the M. koenigii plant.…”

“…showed murrayakonine A (IC 50 10 µM), murrayanine (IC 50 9.4 µM), and O-methylmurrayamine-A (IC 50 7 µM) against TNF-α, and murrayanine (IC 50 8.4 µM) and methylmurrayamine-A (IC 50 8.4 µM) against IL-617.9 µM MCF-7 cells O-methylmurrayamine A exhibited anti-colon cancer activity through downregulation of the Akt/mTOR survival pathway and activation of the intrinsic pathway of apoptosis Mahanine increased the expression of LC3B-II, cleaved caspase-3 proteins, and the inhibition of autophagic flux [to be mainly due to the induction of apoptosis and cell cycle arrest due to the inhibition of the PI3K/AKT/mTOR and Wnt/b-catenin signaling pathways in MCF7 cells that was mediated by cell death and regulated the mitochondrial membrane potential by downregulating Bcl2 and upregulating Bax, due to cytochrome c release from the mitochondria to the cytosol, and significantly downregulated the Wnt/β-catenin self-73 µg/mL Prostate cancer stem cells Koenimbin induced apoptosis through the intrinsic signaling pathway and suppression of the translocation of cytoplasmic NF-κB into the nucleus, in addition to displaying potential for targeting PCSCs, as affirmed by the prostasphere formation and Aldefluor cell migration and invasion and inhibited cell growth was simultaneous with the suppression of p-PI3K, p-AKT, and psynergistically displayed growth inhibitory activity in cervical cancer, the inhibition of STAT3 activation, cell migration, and induced apoptosis [14] Anticancer (Lung) Leaves Methanol Mahanine 15 µM NSCLC cancer cell line A549Mahanine induced the impairment of mTORC2 through rictor inhibition and the destruction of NSCLC cancer cells[22] …”

10-Gingerol as an inducer of apoptosis through HTR1A in cumulus cells: In-vitro and in-silico studies

“…Moreover, the loss of RICTOR in oocytes causes follicular apoptotic death, 54 while the deletion of RICTOR in osteoblasts inhibits osteoblast bone formation 114 . Furthermore, the suppression of RICTOR induces apoptosis in lung cancer cells 53 …”

“…Apoptosis is the process of programmed cell death, which can occur either through the extrinsic pathway, which is characterized as death receptor-mediated, 44 and the intrinsic pathway, which is influenced by members of the bcl family (bax and bcl-2) to act as pro- or anti-apoptotic factors depend on the regulatory proteins 45 . The activation of pro-apoptotic proteins, such as FOXO-1 46 , FOXO-3, 47 and PTEN, 48 and the inactivation of anti-apoptotic proteins, such as ILK, 49 MDM2, 50 NOS3, 51 mTOR, 52 and RICTOR,53, 54 leads to apoptosis.…”