Abstract:Objective This study aimed to investigate the effect of SIK2 on cisplatin resistance induced by aerobic glycolysis in breast cancer cells and its potential mechanism. Methods qRT-PCR and Western blot were used to detect SIK2 mRNA and protein levels. Cisplatin (DDP) resistant cell lines of breast cancer cells were established, CCK-8 was used to measure and evaluate the viability, and Transwell was used to evaluate the cell invasion capability. Flow cytometry was adopted to evaluate the apoptosis rate. The glyco… Show more
“…Similarly, also mechanical cues [93] and hypoxia or pseudohypoxia [56 , 94] can promote glycolysis-induced drug resistance. As regards cell-autonomous stimuli, oncoproteins, whether mutated or overexpressed [39 , 47 , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , tumor-associated immune checkpoint molecules [45] and long noncoding (lnc) RNAs/micro (mi) RNAs [16] are examples of stimuli that induce glycolysis-associated drug resistance. Fig.…”
Section: Stimuli Promoting Glycolysis-induced Drug Resistancementioning
confidence: 99%
“…Many of these stimuli lead, directly or indirectly, to the activation of transcription factors that induce the expression of genes encoding glycolytic enzymes. In this regard, the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling pathway [98 , 103 , 104] as well as the transcription factors hypoxia-inducible factor (HIF)-1α and c-Myc [67 , 94 , 96 , 105] play a prominent, but not exclusive [106] role.…”
Section: Stimuli Promoting Glycolysis-induced Drug Resistancementioning
confidence: 99%
“…In fact, apoptosis is the main mechanism for tumor cell death in response to antitumor drugs and, therefore, a molecule that induces drug resistance is expected to have antiapoptotic effects. Antiapoptotic effects have been demonstrated for glycolytic metabolism in general [49 , 98 , 112] and for individual components of it: enzymes like HK2 [16] , PFKFB3 [49] , PFK platelet type P (PFKP) [121] , ENO1 [56 , 95] , PKM2 [18 , 59 , 94 , 109 , 122] , LDHA [123] , PDK isoform 1 (PDK1) [73 , 124] , metabolites like pyruvate [78] , lactate and lactate-induced acidosis [87] . Antiapoptotic effects are achieved in several ways.…”
Section: Mechanisms Underlying Glycolysis-induced Drug Resistancementioning
confidence: 99%
“…In most cases, however, the 2 variables may contribute each, to a variable degree, to drug resistance [15 , 51 , 53 , 56 , 97] . In fact, the expression of a particular isoform of a glycolytic enzyme may be linked to the tumorigenic process per se and its overexpression may be the result of intracellular or extracellular stimuli [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] . Such overexpression would then represent a sufficient condition for setting in motion the molecular mechanisms that ultimately lead to drug resistance.…”
Section: When Do These Mechanisms Come Into Play?mentioning
“…Similarly, also mechanical cues [93] and hypoxia or pseudohypoxia [56 , 94] can promote glycolysis-induced drug resistance. As regards cell-autonomous stimuli, oncoproteins, whether mutated or overexpressed [39 , 47 , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , tumor-associated immune checkpoint molecules [45] and long noncoding (lnc) RNAs/micro (mi) RNAs [16] are examples of stimuli that induce glycolysis-associated drug resistance. Fig.…”
Section: Stimuli Promoting Glycolysis-induced Drug Resistancementioning
confidence: 99%
“…Many of these stimuli lead, directly or indirectly, to the activation of transcription factors that induce the expression of genes encoding glycolytic enzymes. In this regard, the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling pathway [98 , 103 , 104] as well as the transcription factors hypoxia-inducible factor (HIF)-1α and c-Myc [67 , 94 , 96 , 105] play a prominent, but not exclusive [106] role.…”
Section: Stimuli Promoting Glycolysis-induced Drug Resistancementioning
confidence: 99%
“…In fact, apoptosis is the main mechanism for tumor cell death in response to antitumor drugs and, therefore, a molecule that induces drug resistance is expected to have antiapoptotic effects. Antiapoptotic effects have been demonstrated for glycolytic metabolism in general [49 , 98 , 112] and for individual components of it: enzymes like HK2 [16] , PFKFB3 [49] , PFK platelet type P (PFKP) [121] , ENO1 [56 , 95] , PKM2 [18 , 59 , 94 , 109 , 122] , LDHA [123] , PDK isoform 1 (PDK1) [73 , 124] , metabolites like pyruvate [78] , lactate and lactate-induced acidosis [87] . Antiapoptotic effects are achieved in several ways.…”
Section: Mechanisms Underlying Glycolysis-induced Drug Resistancementioning
confidence: 99%
“…In most cases, however, the 2 variables may contribute each, to a variable degree, to drug resistance [15 , 51 , 53 , 56 , 97] . In fact, the expression of a particular isoform of a glycolytic enzyme may be linked to the tumorigenic process per se and its overexpression may be the result of intracellular or extracellular stimuli [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] , [106] . Such overexpression would then represent a sufficient condition for setting in motion the molecular mechanisms that ultimately lead to drug resistance.…”
Section: When Do These Mechanisms Come Into Play?mentioning
“…It has been reported that salt-inducible kinase 2 (SIK2) is upregulated in breast ( 20 ), ovarian ( 21 ) and cervical cancer ( 22 ), and promotes cancer progression, thus suggesting that SIK2 may act as an oncogene. To the best of our knowledge, the role of SIK2 in CRC has not been previously reported.…”
Colorectal cancer (CRC) is the third most common type of cancer worldwide. Currently, surgery, chemotherapy and radiation therapy are the conventional approaches used to treat CRC. However, these therapy strategies cause several side effects. The present study aimed to develop an alternative and more effective treatment approach for patients with CRC. It has been reported that salt-inducible kinase 2 (SIK2) acts as an oncogene. Therefore, in the present study, the expression levels of SIK2 were determined in CRC cells using western blot analysis and reverse transcription-quantitative PCR. In addition, SIK2 was knocked down in CRC cells to evaluate its role in cell proliferation, migration, invasion and glycolysis using Cell Counting Kit-8, wound healing, Transwell assays and glycolysis cell-based assay kit, respectively. Additionally, the target genes of SIK2 were identified using bioinformatics analysis, while SIK2 overexpression experiments were carried out to determine whether SIK2 could regulate CRC cell malignant behavior and glycolysis. The results revealed that SIK2 was upregulated in CRC cells. Furthermore, SIK2 knockdown attenuated CRC cell proliferation, migration, invasion and glycolysis. Bioinformatics analysis predicted that SIK2 could interact with tripartite motif containing 28 (TRIM28), while TRIM28 overexpression could reverse the effects of SIK2 silencing on cell proliferation, migration, invasion and glycolysis. This finding indicated that the aforementioned effects of SIK2 were mediated by regulating TRIM28. In conclusion, the findings of the present study suggested that SIK2 may be involved in CRC carcinogenesis and glycolysis by regulating TRIM28 expression. These findings could provide a novel approach to targeted therapy and clinical diagnosis of CRC in the future.
Excessive hepatic lipid accumulation is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A previous study showed that the circular RNA (circRNA) PTK2 was significantly downregulated in NAFLD mice. However, the detailed function of circ PTK2 in NAFLD remains unclear. A high‐fat diet (HFD) was used to establish a mouse model of NAFLD, and free fatty acid (FFA) treatment was used to establish an in vitro model of NAFLD. Oil red O staining was used to evaluate lipid accumulation. The pathological changes in mice were observed by HE staining. Western blotting and RT–qPCR were applied to assess protein and mRNA levels, respectively. A dual luciferase reporter assay and RIP were used to explore the relationship among circ PTK2, miR‐200c and SIK2. Circ PTK2 and SIK2 were downregulated and miR‐200c was upregulated in NAFLD. Upregulation of circ PTK2 reversed lipid accumulation in FFA‐treated HepG2 cells. Moreover, circ PTK2 bound to miR‐200c, and SIK2 was identified as the direct target of miR‐200c. Moreover, the miR‐200c inhibitor‐induced decrease in lipid accumulation was reversed by SIK2 knockdown. Furthermore, the impact of circ PTK2 overexpression on PI3K/Akt signaling was partially reversed by SIK2 silencing. Circ PTK2 overexpression alleviates NAFLD development via the miR‐200c/SIK2/PI3K/Akt axis. Thus, our work might provide new methods for NAFLD treatment.
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