Targeting transient receptor potential canonical 1 reduces non‑small cell lung cancer chemoresistance and stemness via inhibition of PI3K/AKT signaling

by Selleckchem | Jul 03 2023

TRPC1 enhances cell proliferation and migration in non-small cell lung cancer (NSCLC); however, its effect on NSCLC chemoresistance and stemness remains to be determined. The aim of the current study was to investigate the effect of TRPC1 on NSCLC chemoresistance and stemness and to determine the underlying mechanism of action. Cisplatin-resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were first established and were then transfected with negative control small interfering (si)RNA (si-NC) or TRPC1 siRNA (si-TRPC1). Cells were then treated with 740 Y-P, a PI3K/Akt agonist. Subsequently, the sensitivity of A549/CDDP and H460/CDDP cells to CDDP was evaluated. Furthermore, the expression levels of CD133 and CD44, and sphere formation ability were also determined. The results showed that the half-maximal inhibitory concentration (IC50) of CDDP was significantly higher in A549/CDDP cells compared with A549 cells and in H460/CDDP cells compared with H460 cells. TRPC1 silencing decreased the IC50 value of CDDP compared with the si-NC group in A549/CDDP (11.78 vs. 21.58 µM; P<0.01) and H460/CDDP (23.76 vs. 43.11 µM; P<0.05) cells. Additionally, TRPC1 knockdown in both cell lines decreased the number of spheres formed compared with the si-NC group. Furthermore, compared with the si-NC group, A549/CDDP cells transfected with si-TRPC1 exhibited decreased levels of both CD133 (P<0.01) and CD44 (P<0.05). However, only CD133 (P<0.05) was downregulated in TRPC1-depleted H460/CDDP cells compared with the si-NC group. In addition, TRPC1 knockdown repressed PI3K/AKT signaling compared with the si-NC group in both A549/CDDP and H460/CDDP cells (all P<0.05). Finally, cell treatment with 740 Y-P reversed the effect of TRPC1 knockdown on PI3K/AKT signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells (all P<0.05). In conclusion, the results of the current study suggested that targeting TRPC1 could attenuate cancer stemness and chemoresistance via suppression of PI3K/AKT signaling in NSCLC.

Comments:

The study aimed to investigate the effect of TRPC1 (Transient Receptor Potential Canonical 1) on chemoresistance and stemness in non-small cell lung cancer (NSCLC) and determine the underlying mechanism of action. Cisplatin-resistant A549 (A549/CDDP) and H460 (H460/CDDP) cells were established and transfected with negative control small interfering RNA (si-NC) or TRPC1 siRNA (si-TRPC1). The cells were then treated with 740 Y-P, a PI3K/Akt agonist, and various analyses were performed.

The results showed that the IC50 (half-maximal inhibitory concentration) of cisplatin (CDDP) was significantly higher in A549/CDDP cells compared to A549 cells and in H460/CDDP cells compared to H460 cells. Silencing TRPC1 decreased the IC50 value of CDDP in both A549/CDDP and H460/CDDP cells compared to the si-NC group. This suggests that TRPC1 may contribute to chemoresistance in NSCLC.

TRPC1 knockdown also reduced the number of spheres formed, which is indicative of cancer stemness, in both cell lines compared to the si-NC group. Furthermore, the expression levels of CD133 and CD44, which are markers of cancer stem cells, were decreased in A549/CDDP cells transfected with si-TRPC1 compared to the si-NC group. In H460/CDDP cells, only CD133 expression was downregulated in TRPC1-depleted cells compared to the si-NC group.

Additionally, TRPC1 knockdown suppressed PI3K/Akt signaling in both A549/CDDP and H460/CDDP cells. This suggests that TRPC1 may activate the PI3K/Akt pathway, which is known to be involved in promoting cell survival, proliferation, and chemoresistance.

Furthermore, treatment with 740 Y-P reversed the effects of TRPC1 knockdown on PI3K/Akt signaling, chemoresistance, and cancer stemness in A549/CDDP and H460/CDDP cells. This indicates that the activation of PI3K/Akt signaling may be involved in mediating the effects of TRPC1 on chemoresistance and stemness.

In conclusion, the study suggests that targeting TRPC1 could attenuate cancer stemness and chemoresistance in NSCLC by suppressing PI3K/Akt signaling. These findings provide insights into the potential therapeutic strategies for overcoming chemoresistance and targeting cancer stem cells in NSCLC.