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.

• Authors: Priyajit Chatterjee, Soma Seal, Sandip Mukherjee, Rakesh Kundu, Mantu Bhuyan, Nabin C Barua, Pranab K Baruah, Santi Prasad Sinha Babu, Samir Bhattacharya
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 405 Issue 1-2 Pg. 149-58 (Jul 2015) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 25893736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Carbazoles
• Carrier Proteins
• RICTOR protein, human
• Rapamycin-Insensitive Companion of mTOR Protein
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Alkaloids (pharmacology)
• Apoptosis (drug effects)
• Carbazoles (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Humans
• Lung Neoplasms (drug therapy, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rapamycin-Insensitive Companion of mTOR Protein
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)