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.