HSPA12B overexpression induces cisplatin resistance in non-small-cell lung cancer by regulating the PI3K/Akt/NF-κB signaling pathway

Abstract

Abstract. Although cisplatin (CDDP) is widely used for non-small-cell lung cancer (NSCLC) treatment, resistance remains a major problem that restricts its efficacy. Therefore, identification of drugs that reverse or prevent resistance to CDDP in NSCLC has been a focus of a number of studies. The results of the present study revealed the effect of heat shock protein family A member 12B (HSPA12B) overexpression on chemoresistance in A549 cells in vitro. The effect of HSPA12B overexpression on chemoresistance in mice bearing A549 xenografted tumors was then determined via stable HSPA12B transfection. Finally, the effects of HSPA12B overexpression on the phosphorylation of protein kinase B (Akt) and nuclear factor-κB inhibitor α (IκBα), and the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the pro-apoptotic protein cleaved caspase-3 were determined by western blot analysis. The results demonstrated that HSPA12B overexpression increased resistance to CDDP in NSCLC cells in vivo and in vitro by promoting cell growth and inhibiting CDDP-induced apoptosis. Mechanistically, this effect was mediated by the upregulation of phosphorylated (p-)Akt, p-IκBα and Bcl-2 and the downregulation of cleaved caspase-3. Therefore, the present study provides useful information pertaining to the identification and targeting of a CDDP-resistant population, and the development of potential therapeutics to improve the current treatment modalities in NSCLC.

<p>HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling</p>

“…Previous studies found that HSPA12B is a potential activator of PI3K/Akt/mTOR signaling in endothelial cells and in some cancer cells. 23 , 24 Actually, activation of the PI3K/Akt/mTOR signaling is critical for M2 polarization of macrophages. 25 Therefore, we further assessed whether exogenous HSPA12B could activate the PI3K/Akt/mTOR signaling in macrophages.…”

“…Transgenic mice overexpressing HSPA12B subjected to xenograft lung tumor models have significantly upregulated expression of VEGF and angiopoietin-1 and enhanced eNOS phosphorylation compared with wild-type counterparts. 26 Its upregulation induces chemo-resistance in non-small-cell lung cancer 24 and cervical squamous cell carcinoma. 27 However, as a modulator of immune responses in endothelial cells, its functional role in tumor immune microenvironment has not yet been explored.…”

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…The PI3K/AKT/NF-κB pathway affected the expression of Bcl-2 and caspase-3, which was cleaved by apoptotic proteins. These alterations regulated NSCLC cell growth and apoptosis to promote MDR 70 . Abnormal activation of the PI3K/AKT/NF-κB signaling pathway also regulated the expression of P-gp to achieve MDR, which is discussed in the following sections 23 .…”

Inactivation of AKT/NF‑κB signaling by eurycomalactone decreases human NSCLC cell viability and improves the chemosensitivity to cisplatin

“…The AKT/NF-κB signaling pathway is constitutively activated in several types of cancer, including NSCLC ( 6 ). Furthermore, the high AKT/NF-κB activation has also been demonstrated as a key mechanism of acquired cisplatin resistance by increasing the threshold for cell death induction ( 8 , 9 ). Exposure to cisplatin activates AKT/NF-κB signaling, which consequently induces the expression of NF-κB target genes, including anti-apoptotic genes and genes involved in cell survival, such as Bcl-xL and survivin.…”