Reversing effect and mechanism of soluble resistance-related calcium-binding protein on multidrug resistance in human lung cancer A549/DDP cells

Abstract

Abstract. Lung cancer is the primary malignancy of the lung and is the leading cause of cancer-associated mortality in China. Multidrug resistance (MDR) is an essential aspect of lung cancer treatment failure and a popular topic of investigation in tumor studies. Previous studies have demonstrated that soluble resistance-related calcium-binding protein (Sorcin) is involved in the MDR of various types of human tumor, and that silencing Sorcin was able to reverse the MDR of several types of cultured human cancer cells. However, the effect and potential mechanism underlying the ability of Sorcin to reverse MDR in human lung cancer remains to be fully elucidated. The present study examined the role of Sorcin in the reversal of MDR in human lung cancer A549/DDP cells. The effects included increased drug sensitivity to cisplatin, apoptotic rate, cell cycle arrest in the G2/M phase and intracellular accumulation of rhodamine-123, and decreased expression of multidrug resistance gene 1, lung resistance protein, multidrug resistance-associated protein, glutathione S-transferase π, ATP-binding cassette transporter A2 (ABCA2), ABCA5, B-cell lymphoma 2 and P-glycoprotein, and the depletion of glutathione in Sorcin-silenced A549/DDP cells. The present study also revealed that there was a downregulation of p-Akt and phosphorylated extracellular signal-regulated kinase (p-ERK), and a decreased transcriptional activation of nuclear factor κB, signal transducer and activator of transcription (STAT)3, STAT5 and nuclear factor of activated T-cells following silencing of Sorcin. The results indicated that Sorcin may be used as a potential therapeutic target for MDR through inhibiting the Akt and ERK pathways in human lung cancer.

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

“…Sorcin is overexpressed in a number of cancers, such as lymphoma, leukemia (acute lymphoblastic, acute myeloid, chronic myeloid leukemias), myeloma, breast cancer, adenocarcinoma, gastric cancer, colorectal cancer, nasopharyngeal cancer, lung tumor, ovarian cancer, prostate cancer, tobacco-chewing mediated oral cancer, and particularly in MD-resistant tumors [20,[24][25][26]34,[50][51][52][53][54][55][56][57][58][59][60]; sorcin is overexpressed in glioblastoma, anaplastic astrocytoma, and oligodendroglioma, while is an important marker of poor clinical outcome in embryonal central nervous system tumors and a histological marker for malignant glioma [61][62][63][64][65]. According to the Human Protein Atlas (https://www.proteinatlas.org/ENSG00000075142-SRI), sorcin has moderate to strong cytoplasmic and nuclear positivity in most cancers, with the strongest staining displayed in low-grade gliomas, and is an unfavorable prognostic marker (p < 0.001) in pancreatic cancer (unfavorable), and an unfavorable quasi-marker (0.001 < p < 0.003) for liver cancer, cervical cancer, and endometrial cancer.…”

“…Sorcin transfection in different cancer cell lines, such as leukemia, lung, gastric, ovarian, and breast tumors, leads to increased drug resistance to chemotherapeutic drugs such as doxorubicin, vincristine, paclitaxel, etoposide, homoharringtonine, and 5-fluorouracil [24,25,34,60,66,75,98,99]. Conversely, sorcin silencing reverses MDR in leukemia, HeLa, breast, and colorectal cancer and nasopharyngeal carcinoma [24,26,52,54,60,[66][67][68][69][70]. Human colorectal cancer cells express high amounts of sorcin, whose upregulation induces resistance to oxaliplatin, 5-fluorouracil, and irinotecan, while its downregulation sensitizes cells towards these drugs [26].…”

“…Human colorectal cancer cells express high amounts of sorcin, whose upregulation induces resistance to oxaliplatin, 5-fluorouracil, and irinotecan, while its downregulation sensitizes cells towards these drugs [26]. Sorcin is upregulated in many cisplatin-resistant cancers and tumor cell lines, such as leukemia, nasopharyngeal carcinoma, and lung cancer, while sorcin silencing increases cisplatin cytotoxicity and glutathione depletion [54,69,71]. Silencing of sorcin in MD-resistant myeloma cell lines increases cellular sensitivity to cisplatin and adriamycin, and decreases cell proliferation, cell cycle blockage, and apoptosis [32].…”

Targeting P‐glycoprotein and SORCIN: Dihydromyricetin strengthens anti‐proliferative efficiency of adriamycin via MAPK/ERK and Ca2+‐mediated apoptosis pathways in MCF‐7/ADR and K562/ADR

“…SORCIN is highly expressed in some mammalian normal tissues such as heart (Suarez et al, ) and brain (Kim, Lee, Kim, Kwon, & Chun, ), and overexpresses in various cancer multidrug‐resistance cells (Mangia et al, ; Meyers, Schneider, Spengler, Chang, & Biedler, ). SORCIN participates in the formation of drug resistance in tumoral cells (Gao, Li, Liu, Gao, & Zhao, ). Apparently, increased expression of SORCIN is closely associated with drug resistance and poor prognosis in clinical studies (Dabaghi et al, ).…”

Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents

“…Sorcin is overexpressed in many human cancers, including adenocarcinoma, breast cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, hepatocellular carcinoma and ovarian cancer, lymphoma, leukemia and myeloma, and particularly in cancers with ABCB1-dependent MD-resistant phenotype [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] . The level of expression of Sorcin is one of the main markers of poor outcome in embryonal tumors of central nervous system [82] ; Sorcin is a histological marker for malignant glioma, and is overexpressed in anaplastic astrocytoma, glioblastoma and oligodendroglioma [83][84][85][86] .…”