The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation

Fan, Guangjian; Sun, Lianhui; Meng, Ling; Hu, Chen; Wang, Xing; Shi, Zhan; Hu, Congli; Yang, Qingqing; Cao, Liu; Zhang, Xiaohong; Zhang, Yan; Song, Xianmin; Xia, Shujie; He, Baokun; Zhang, Shengping; Wang, Chuangui

doi:10.1038/s41467-020-20208-x

Cited by 53 publications

(46 citation statements)

References 52 publications

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“…CRC xenografts were established in 5-week-old female BALB/c nude mice purchased from the Institute of Zoology, Chinese Academy of Sciences, Shanghai. Tumor-bearing and the calculation of tumor volumes were performed as previously described [ 32 ]. Briefly, SHMT2-sh and control cells (3 × 10 6 ) were injected subcutaneously into the flanks of nude mice.…”

Section: Methodsmentioning

confidence: 99%

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The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Chen

Xiao³

et al. 2021

Oncogene

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Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

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Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed as previously described [ 32 ]. The intensity and extent of staining were evaluated independently by two pathologists blinded to the patient outcomes.…”

Section: Methodsmentioning

confidence: 99%

The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Chen

Xiao³

et al. 2021

Oncogene

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“…A recent study has shown that KIFC1 phosphorylation induces chromosomal instability in breast cancer [ 31 ]. As shown in Figure 3 C, KIFC1 expression was increased in genomically unstable type BC in the IMvigor 210 study.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have shown that KIFC1 is involved in cisplatin resistance in breast cancer [ 31 , 35 ]. Therefore, we analyzed the involvement of KIFC in cisplatin resistance in BC.…”

Section: Resultsmentioning

confidence: 99%

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KIFC1 Is Associated with Basal Type, Cisplatin Resistance, PD-L1 Expression and Poor Prognosis in Bladder Cancer

Sekino

Pham

Kobatake

et al. 2021

JCM

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Kinesin family member C1 (KIFC1), a minus end-directed motor protein, is reported to play an essential role in cancer. This study aimed to analyze KIFC1 expression and examine KIFC1 involvement in cisplatin resistance in bladder cancer (BC). Immunohistochemistry showed that 37 of 78 (47.4%) BC cases were positive for KIFC1. KIFC1-positive cases were associated with high T stage and lymph node metastasis. Kaplan-Meier analysis showed that KIFC1-positive cases were associated with poor prognosis, consistent with the results from public databases. Molecular classification in several public databases indicated that KIFC1 expression was increased in basal type BC. Immunohistochemistry showed that KIFC1-positive cases were associated with basal markers 34βE12, CK5 and CD44. KIFC1 expression was increased in altered TP53 compared to that in wild-type TP53. Immunohistochemistry showed that KIFC1-positive cases were associated with p53-positive cases. P53 knockout by CRISPR-Cas9 induced KIFC1 expression in BC cell lines. Knockdown of KIFC1 by siRNA increased the sensitivity to cisplatin in BC cells. Kaplan-Meier analysis indicated that prognosis was poor among KIFC1-positive BC patients treated with cisplatin-based chemotherapy. Immunohistochemistry showed that KIFC1-positive cases were associated with PD-L1-positive cases. High KIFC1 expression was associated with a favorable prognosis in patients treated with atezolizumab from the IMvigor 210 study. These results suggest that KIFC1 might be a promising biomarker and therapeutic target in BC.

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X‐Ray‐Responsive Zeolitic Imidazolate Framework‐Capped Nanotherapeutics for Cervical Cancer‐Targeting Radiosensitization

Pan

Huang

Sun

et al. 2023

Adv Funct Materials

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Developing radiosensitizers based on the characteristics of the tumor microenvironment can improve the effectiveness and overcome the bottleneck of cervical cancer radiotherapy. Herein, an in situ synthesis strategy is demonstrated by using a highly bioactive zeolitic imidazolate framework to cap Mn 3 O 4 and folic acid as targeting molecules (FA-Mn 3 O 4 @ZIF-8) to achieve enhanced radiosensitization against cervical cancer. As expected, the ZIF-8 cap on the surface of Mn 3 O 4 responds more effectively to X-rays. Meanwhile, by facilitating the presence of oxygen vacancies and valence transition of manganese on the surface of Mn 3 O 4 , the ZIF-8 cap on Mn 3 O 4 can increase the catalytic capacity for hydrogen peroxide (H 2 O 2 ) and glutathione as well as produce more singlet oxygen under X-ray, alleviate hypoxia within the tumor microenvironment, and increase reactive oxygen species production. Moreover, FA-Mn 3 O 4 @ZIF-8 shows excellent radiotherapy-sensitizing properties in vitro and in vivo by promoting DNA damage and apoptosis. Collectively, this study suggests that designing and construction of X-ray responsive nanoradiosensitizers could be a good way for future clinical radiotherapy of malignant cervical cancer.

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The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation

Cited by 53 publications

References 52 publications

The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

KIFC1 Is Associated with Basal Type, Cisplatin Resistance, PD-L1 Expression and Poor Prognosis in Bladder Cancer

X‐Ray‐Responsive Zeolitic Imidazolate Framework‐Capped Nanotherapeutics for Cervical Cancer‐Targeting Radiosensitization

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