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  • Along with the improvement of

    2023-01-16

    Along with the improvement of the cadmium transport from roots to aerial tissues, as is required for phytoremediation, over-expression of PtoHMA5 also led to the excessive accumulation of cadmium in leaves that was harmful to plant growth and physiological performance. Thus, detoxification of the heavy metal ions associated with breeding HMA transgenic plants is the other challenge in future. Fortunately, several other genes such as PCS, MTs, and NRAMPs have been found to function indetoxification but have a lower potential for long distance transportation of heavy metal ions [40].Therefore, cooperation of these various genes are likely to be necessary to improve phytoremediation.
    Conclusion PtoHMA5, a typical Cu2+-ATPase, could efficiently advance the Cd2+ transport by 33.51% averagely in transgenic tobacco plants, but also lead to excessive accumulation of cadmium in leaves and caused the sharp decrease of plant resistance to cadmium. Polymerization breeding of PtoHMA5 and PtPCS genes was suggested to satisfy certain requirement of phytoremediation.
    Introduction Clusterin (CLU) is a disulfide-linked heterodimeric protein that has been implicated in various cell functions involved in pathophysiological processes, including tissue remodeling, reproduction, lipid transport, complement regulation, and apoptosis [1]. CLU has been reported as an anti-apoptotic and pro-apoptotic factor, and these ambiguous functions are caused by two protein isoforms through alternative splicing, including a secreted form (sCLU) and nuclear form (nCLU) [2]. sCLU is a cytoprotective protein that is upregulated after exposure to chemotherapy and radiotherapy [[3], [4], [5]]. The expression level of sCLU is significantly correlated with tumor aggressiveness, chemotherapy and radiotherapy resistance and poor patient prognosis, thereby identifying sCLU as a therapeutic target for cancer. The hypoxic and acidic tumor environment induces the selection of tumor GSK2245840 able to survive in this unfavorable environment and contributes to the progression from benign to malignant growth [6]. Tumor acidity, in particular, has been shown to have a role in resistance to chemotherapy, proliferation, and metastatic behavior [[7], [8], [9]]. The maintenance of the acidic pH of the tumor involves vacuolar-ATPase (V-ATPase) [10]. The role of V-ATPase is to pump protons from the cytosol into intracellular compartments or the extracellular space [11,12]. The expression of V-ATPase is associated with invasive and chemoresistant phenotypes [13,14] and with increased proliferative activity [9,15]. Thus, V-ATPase inhibitors, including bafilomycin A1 and concanamycin A, have been suggested as potential anticancer agents [16,17].
    Materials and methods
    Results
    Discussion sCLU is a cytoprotective protein that is upregulated after exposure to chemotherapy and radiotherapy [[3], [4], [5]] and confers resistance to therapy when overexpressed, thereby identifying sCLU as a therapeutic target for cancer. In this study, we found that the V-ATPase inhibitors bafilomycin A1 and concanamycin A induced sCLU protein expression in a dose-dependent manner (Fig. 1). Knockdown of sCLU with siRNA enhanced the sensitivity of NSCLCs to bafilomycin A1 (Fig. 2B and C), suggesting that the suppression of sCLU improves the efficacy of V-ATPase inhibitors. sCLU silencing using antisense oligonucleotides or siRNA was found to result in increased sensitivity to chemotherapy and radiotherapy and a decreased metastatic potential in lung cancer cell lines [3,4,[24], [25], [26]]. The PI3K/AKT/mTOR pathway is a key oncogenic signaling pathway that has been linked to tumorigenesis and resistance to anticancer therapies, and its down-regulation lowers resistance to chemotherapy in tumor cells [27,28]. In our study, we found that when sCLU protein was increased by bafilomycin A1, AKT phosphorylation was also induced by bafilomycin A1. However, bafilomycin A1 suppressed mTOR activity, as evidenced by the decreased phosphorylation of S6. We have previously shown that mTOR inhibition enhances AKT activation and contributes to cisplatin resistance in NSCLC cells, and we proposed that dual blockade of PI3K/AKT and mTOR may be an effective strategy for improving the efficacy of anticancer treatments [22]. BEZ235 is an orally administered dual PI3K/AKT and mTOR kinase inhibitor. We found that BEZ235 blocked the sCLU protein expression and further enhanced the induction of PARP cleavage and the reduction of cell viability in bafilomycin A1-treated cells (Fig. 3B and C). Mcl-1 and survivin are regulated in an mTORC1-mediated cap-dependent manner [23]. As expected, BEZ235 decreased the levels of Mcl-1 and survivin protein in a dose-dependent manner (Fig. 3A). The combination of BEZ235 and bafilomycin A1 led to a dramatic decrease in survivin expression, but not Mcl-1 expression (Fig. 3B). Overexpression of survivin alleviated the sensitivity of the NSCLC cells by bafilomycin A1 and sCLU depletion, suggesting that the increased sensitivity of the NSCLC cells treated with bafilomycin A1 in combination with sCLU depletion is due, at least in part, to the down-regulation of survivin. Taken together, our results indicate that the suppression of sCLU enhances the sensitivity of NSCLC cells to V-ATPase inhibitors and suggest that a combination of PI3K/AKT/mTOR inhibitors with V-ATPase inhibitors be an effective approach for NSCLC treatment.