Silencing of Twist1 sensitizes NSCLC cells to cisplatin via AMPK-activated mTOR inhibition

Abstract

Twist1 is highly expressed in primary and metastatic non-small cell lung cancer (NSCLC), and thus acts as a critical target for lung cancer chemotherapy. In the current study, we investigated the underlying mechanism initiated by silencing of Twist1 that sensitizes NSCLC cells to cisplatin. Silencing of Twist1 triggered ATP depletion, leading to AMP-activated protein kinase (AMPK)-activated mammalian target of rapamycin (mTOR) inhibition in NSCLC cells. AMPK-induced mTOR inhibition, in turn, resulted in downregulation of ribosome protein S6 kinase 1 (S6K1) activity. Downregulation of mTOR/S6K1 reduced Mcl-1 protein expression, consequently promoting sensitization to cisplatin. Overexpression of Mcl-1 reduced PARP cleavage induced by cisplatin and Twist1 siRNA, suggesting that this sensitization is controlled through Mcl-1 expression. Interestingly, cells treated with Twist1 siRNA displayed upregulation of p21Waf1/CIP1, and suppression of p21Waf1/CIP1 with specific siRNA further enhanced the cell death response to cisplatin/Twist1 siRNA. In conclusion, silencing of Twist1 sensitizes lung cancer cells to cisplatin via stimulating AMPK-induced mTOR inhibition, leading to a reduction in Mcl-1 protein. To our knowledge, this is the first report to provide a rationale for the implication of cross-linking between Twist1 and mTOR signaling in resistance of NSCLC to anticancer drugs.

Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF‐κB‐mediated IKKβ expression

“…TWIST1 promotes resistance to apoptosis when cells are challenged with cisplatin in lung, bladder, and ovarian cancer, or paclitaxel in ovarian and prostate cancers . Here, we observed that COL11A1 interfered with cisplatin and paclitaxel‐induced apoptosis in ovarian cancer cells by upregulating NF‐κB/TWIST1‐mediated Mcl‐1 and GAS6 expression.…”

“…Mcl‐1 has been shown to be a critical survival factor in ovarian cancer . Previous findings also indicated that TWIST1 knockdown enhances the sensitivity of cells to cisplatin through Mcl‐1 downregulation, which is linked to inhibited mTOR activity in lung cancer cells . GAS6 is known to inhibit apoptosis and GAS6 upregulation is a marker for poor prognosis in ovarian cancer .…”

Vaccine-Mediated Immunotherapy Directed against a Transcription Factor Driving the Metastatic Process

“…While tumor cells with high levels of Twist presented F-actin filaments organized into actin stress fibers, silencing of Twist in 4T1 cells promoted cortical organization of F-actin in the areas of cell-to-cell contact. Although Twist was previously implicated in apoptotic evasion 43, in the 4T1 model, however, silencing Twist did not improve cells’ sensitivity to radiation or docetaxel treatment (data not shown). Altogether, our data indicate that Twist plays a functional role in the 4T1 model on the remodeling of the extracellular matrix as well as on the events of tumor cell migration and invasion.…”

Mithramycin A induces apoptosis by regulating the mTOR/Mcl-1/tBid pathway in androgen-independent prostate cancer cells

“…(17) Several studies have established that the activation of Akt/mTOR signaling is strongly associated with advanced prostate tumors. (18–20) Kremer et al (21) also reported a marked increased in the expression level of mTOR signaling pathway in prostate cancer tissues.…”