Secreted protein acidic and rich in cysteine enhances the chemosensitivity of pancreatic cancer cells to gemcitabine

Fan, Xiaoxuan; Mao, Zhuo‐Ya; Ma, Xiaoyan; Cui, Lei; Qu, Junle; Lv, Lihui; Dang, Sheng-Chun; Wang, Xuqing; Zhang, Jianxin

doi:10.1007/s13277-015-4044-4

Cited by 5 publications

(6 citation statements)

References 16 publications

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“…Secreted protein, acidic and rich in cysteine (SPARC), appears to have opposing effects to GRP78, in that it functions as a chemo-sensitizer in certain cancers, such as CRC 11–13 , hepatocellular carcinoma 14 , pancreatic cancer 15 , and osteosarcoma 16 . SPARC has been demonstrated to suppress cell cycle progression in both ovarian carcinoma 17 and acute myeloid leukemia 18 .…”

Section: Introductionmentioning

confidence: 99%

The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer

et al. 2019

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Therapy-refractory disease is one of the main contributors of treatment failure in cancer. In colorectal cancer (CRC), SPARC can function as a sensitizer to conventional chemotherapy by enhancing apoptosis by interfering with the activity of Bcl-2. Here, we examine a novel mechanism by which SPARC further potentiates apoptosis via its modulation of the unfolded protein response (UPR). Using mass spectrometry to identify SPARC-associated proteins, GRP78 was identified as a protein partner for SPARC in CRC. In vitro studies conducted to assess the signaling events resulting from this interaction, included induction of ER stress with tunicamycin, 5-fluorouracil (5-FU), and irinotecan (CPT-11). We found that the interaction between GRP78 and SPARC increased during exposure to 5-FU, CPT-11, and tunicamycin, resulting in an attenuation of GRP78’s inhibition of apoptosis. In addition, we also show that SPARC can sensitize CRC cells to PERK/eIF2α and IRE1α/XBP-1 UPR signaling by interfering with ER stress following binding to GRP78, which leads to ER stress-associated cell death in CRC cells. In line with these findings, a lower expression of GRP78 relative to SPARC in CRC is associated with a lower IC 50 for 5-FU in either sensitive or therapy-refractory CRC cells. Interestingly, this observation correlates with tissue microarray analysis of 143 human CRC, where low GRP78 to SPARC expression level was prognostic of higher survival rate ( P = 0.01) in individuals with CRC. This study demonstrates that modulation of UPR signaling by SPARC promotes ER stress-associated death and potentiates apoptosis. This may be an effective strategy that can be combined with current treatment options to improve therapeutic efficacy in CRC.

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Section: Introductionmentioning

confidence: 99%

The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer

et al. 2019

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“…[32][33][34][35][36][37][38][39][40][41][42] Also, in vitro and in vivo studies have demonstrated that overexpression of some domains of SPARC leads to a significantly greater chemosensitivity and tumor regression. 36,42 More recently, Fan et al 43 demonstrated that overexpression of SPARC increased the apoptosis in pancreatic cancer cells. These data offer perception on the role accomplished by SPARC in drug sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Secreted protein acidic and rich in cysteine gene variants: Impact on susceptibility and survival of hepatocellular carcinoma patients

Darweesh

Alziz

Omar

et al. 2018

J of Gastro and Hepatol

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Background and Aim Secreted protein acidic and rich in cysteine (SPARC) is a glycoprotein involved in extracellular matrix remodeling, which regulates cell growth. It could be involved in hepatic fibrogenesis related to chronic inflammations, hepatocellular carcinoma (HCC) angiogenesis, and tumor progression. We aimed to study the expressions of single nucleotide polymorphisms in the SPARC gene and their impact on susceptibility and survival of HCC patients. Methods We conducted a case–control study on 200 HCC patients and 50 matched healthy controls. All patients were subjected to laboratory investigations, ultrasound, and real‐time polymerase chain reaction to detect the genetic polymorphisms (rs3210714, rs11950384, and rs7719521) in the SPARC gene in the blood. Results One hundred sixty (80%) patients were men with a mean age of 43 years. The SPARC gene showed a significant higher prevalence of rs3210714 mutation (i.e. AA or AG) and a significant lower prevalence of rs11950384 mutation (i.e. AA or AC) among HCC patients in comparison with controls (83% vs 22%, P ≤ 0.001) and (65.5 vs 86%, P = 0.005), respectively, while rs7719521 mutation did not reach significance. On univariate and multivariate analyses, elder age and having at least one copy of the mutant rs3210714 were associated with a significantly increased risk of HCC (P < 0.001 for both), whereas the presence of at least one copy of the mutant rs11950384 carried a significantly reduced risk of having HCC (P < 0.01). Overall survival did not differ significantly between any of the SPARC gene mutation groups. Conclusions The SPARC gene polymorphisms had a diverse impact on the susceptibility of HCC due to its ability to inhibit or promote tumor progression. SPARC gene polymorphisms were not related to survival of our HCC patients, and probably, this needs further analysis of other SPARC gene nucleotides.

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“…Another study demonstrated that increased SPARC expression in primary PAAD cells is also associated with poorer overall and disease-free survival (14). However, SPARC has also been reported to inhibit proliferation, promote apoptosis and enhance the chemosensitivity of pancreatic cancer cells to gemcitabine (15)(16)(17). In general, SPARC presents as an oncogene in clinical studies and is associated with poor prognosis in patients with PAAD (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…In general, SPARC presents as an oncogene in clinical studies and is associated with poor prognosis in patients with PAAD (13,14). However, in biological experimental studies, SPARC is generally presented as a tumour suppressor of PAAD (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…Secondly, the function of SPARC in PAAD needs further clarification, and the contradicting results of clinical and biological research need to be unified. Finally, while stroma-derived SPARC is associated with poor prognosis in patients with PAAD, cancer cell-derived SPARC inhibits the proliferation and chemoresistance of PAAD cells (13,15,17). Whether SPARC produced by tumour stromal cells vs. PAAD cells has the same effects on tumour growth and progression must be investigated.…”

Section: Introductionmentioning

confidence: 99%

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SPARC promotes pancreatic cancer cell proliferation and migration through autocrine secretion into the extracellular milieu

2021

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SPARC is a secreted glycoprotein that plays a complex and multifaceted role in tumour formation and progression. However, whether SPARC is an oncogene or a tumour suppressor is still unclear. Moreover, SPARC demonstrates potential in clinical pancreatic adenocarcinoma (PAAD) treatment, although it has been identified as an oncogene in some studies and a tumor suppressor in others. In the present study, a pan-cancer analysis of SPARC was carried out using The Cancer genome Atlas data, which demonstrated that SPARC was an oncogene in most cancer types and a cancer suppressor in others. In addition, SPARC expression was significantly upregulated in PAAD and associated with poor prognosis. SPARC also promoted the proliferation and migration of PANC-1 and SW1990 cell lines in vitro. SPARC was detected in the culture supernatant of PAAD cells and pancreatic acinar AR42J cells. SPARC regulated PAAD cell proliferation only when secreted into the extracellular milieu, thus explaining why the prognosis of patients with PAAD is correlated with the SPARC expression of both tumour cells and stromal cells. Collectively, the present findings demonstrated that the function of SPARC was associated with tumour type and that SPARC may represent an important oncogene in PAAD that merits further study.

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Secreted protein acidic and rich in cysteine enhances the chemosensitivity of pancreatic cancer cells to gemcitabine

Cited by 5 publications

References 16 publications

The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer

The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer

Secreted protein acidic and rich in cysteine gene variants: Impact on susceptibility and survival of hepatocellular carcinoma patients

SPARC promotes pancreatic cancer cell proliferation and migration through autocrine secretion into the extracellular milieu

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