Inhibition of CD133 Overcomes Cisplatin Resistance Through Inhibiting PI3K/AKT/mTOR Signaling Pathway and Autophagy in CD133-Positive Gastric Cancer Cells

Abstract

Cisplatin is widely used as the standard gastric cancer treatment, but the relapse and metastasis are common as intrinsic or acquired drug resistance. CD133 has been widely known to be associated with chemoresistance in various cancer cells. In this study, we focused on investigating the function and mechanism of CD133 underlying cisplatin resistance in gastric cancer cell line KATO-III. We detected CD133 expression by using quantitative real-time polymerase chain reaction and Western blot and found that expression of CD133 was upregulated in cisplatin resistance of KATO-III cells (Cis-KATO-III) compared with KATO-III cells, indicating the role of CD133 in regulating cisplatin resistance of KATO-III cells. Then we sorted the Cis-KATO-III cells into CD133-positive (CD133+) pools and measured the proliferation and apoptosis after the cell is transfected with pc-CD133 and sh-CD133 by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and flow cytometry. The results showed that the inhibition of CD133 inhibited the cell viability and promoted the cell apoptosis after cisplatin treatment. Furthermore, we found that inhibition of CD133 downregulated the expression of PI3K/AKT and promoted the expression of mammalian target of rapamycin, thus inhibited the autophagic activity in the Cis-KATO-III cells after cisplatin treatment. Besides, we also verified the effects of CD133 in vivo. The results indicated that inhibition of CD133 enhanced the Cis-KATO-III cell sensitivity to cisplatin by regulating PI3K/AKT/mTOR signaling pathway. In summary, our data provide new insight that CD133 activates the PI3K/AKT/mTOR signaling transduction pathway, resulting in activation of autophagy and cisplatin resistance of Cis-KATO-III cells. These results may offer a novel therapeutic target in cisplatin-resistant gastric cancer.

Retracted Article: Macrophage-derived exosomes mediate osteosarcoma cell behavior by activating AKT signaling

“…28,29 The increased expression of the phosphorylate-type AKT, that is the activation of AKT signaling, is observed in the osteosarcoma cells. 30 It has been reported that the AKT-related signaling pathway mediates drug-resistance in various cancers, such as in gastric cancer 31 and in breast cancer, 32 as well as in osteosarcoma cells. 33 In this research, we found that both PMA-differentiated THP1 and macrophagederived exosomes signicantly increased the expression of phosphorylated AKT, and that the AKT inhibitor MK2206 reversed the effect of the macrophage-derived exosomes, indicating that the macrophage-derived exosomes activated the AKT signaling pathway.…”

<p>STIP1 Regulates Proliferation and Migration of Lung Adenocarcinoma Through JAK2/STAT3 Signaling Pathway</p>

“…In addition, the mechanism through which STIP1 acts on the JAK2/STAT3 signaling pathway also requires further investigation. STIP1, HSP70, and HSP90 are all highly expressed and interact in colon cancer tissue,25 while HSP90 acts on Akt to promote cell growth and inhibit apoptosis 26. STIP1 can also interact with gene promoters; for example, STIP1 can accelerate SMAD protein binding to the ID3 promoter, thereby enhancing ovarian cancer cell proliferation and growth 27.…”

Drug resistance and Cancer stem cells

“…Specific ABCG2 inhibitor Pantoprazole or ABC transporter inhibitor Verapamil can reduce tumor resistance to platinum [16]. It has been reported that CD133 mediates cisplatin resistance that can overcome by inhibition of CD133 [17].…”