Gli1 Protein Regulates the S-phase Checkpoint in Tumor Cells via Bid Protein, and Its Inhibition Sensitizes to DNA Topoisomerase 1 Inhibitors

Tripathi, Kaushlendra; Mani, Chinnadurai; Barnett, Reagan; Nalluri, Sriram; Bachaboina, Lavanya; Rocconi, Rodney P.; Athar, M.; Owen, Laurie B.; Palle, Komaraiah

doi:10.1074/jbc.m114.606483

Cited by 38 publications

(49 citation statements)

References 70 publications

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“…1B). Aberrant Hedgehog (Hh)/Gli signaling is commonly associated with tumor growth, metastasis, and resistance to chemotherapy [16,19] and we previously demonstrated that ALDH1A1 regulates DNA repair and checkpoint progression to enhance resistance to platinum drugs [14]. Therefore, we examined stage 3 and 4 OC and adjacent normal tissue for expression of these proteins in addition to Rad6.…”

Section: Resultsmentioning

confidence: 99%

“…For clonogenic survival assays, 500 cells were plated in 6-well culture dishes in triplicate [16]. Cells were allowed to attach overnight and treated with indicated concentrations of carboplatin or vehicle control (DMSO) overnight.…”

Section: Methodsmentioning

confidence: 99%

“…After the drug treatment cells were washed three times with PBS and two times with growth medium and allowed to form colonies in complete growth medium. After 8 to 12 days colonies were fixed in methanol, stained with crystal violet (0.5% w/v) and counted as described [16]. Only colonies containing more than 25 cells were counted.…”

Section: Methodsmentioning

confidence: 99%

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Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer

Somasagara

Tripathi

Spencer

et al. 2016

Biochemical and Biophysical Research Communications

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Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression. Furthermore, in ovarian cancer cells Rad6 was found to stabilize β-catenin promoting stem cell-related characteristics, including expression of stem cell markers and anchorage-independent growth. Cancer stem cells can promote chemoresistance, tumor recurrence and metastasis, all of which are limiting factors in treating ovarian cancer. Thus it is significant that Rad6 overexpression led to increased resistance to the chemotherapeutic drug carboplatin and correlated with tumor cell invasion. These findings show the importance of Rad6 in ovarian cancer and emphasize the need for further studies of Rad6 as a potential target for the treatment of ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer

Somasagara

Tripathi

Spencer

et al. 2016

Biochemical and Biophysical Research Communications

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“…Yu FY et al found that the molecular mechanisms regulated by the non-canonical Hh pathway mediated through ptch1 and cyclin B1 is involved in the pathogenesis of nevoid basal cell carcinoma syndrome (NBCCS)-associated keratocystic odontogenic tumors (KCOTs) [62]. Tripathi K et al demonstrated that a novel and tumor-specific role for aberrant Gli1 in the regulation of the S-phase checkpoint that suppresses replication stress and resistance to chemotherapy [63]. Therefore, the S phase arrest may be caused by a more significant inhibition in Hh pathway induced by the combination of ATO and CYA.…”

Section: Discussionmentioning

confidence: 99%

Synergism between arsenic trioxide and cyclopamine in the inhibition of PC3 cell survival via the Hedgehog signaling pathway

Yj¹,

Yj²,

Yr³

et al. 2015

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Previous studies have shown that Hh signaling is overexpressed in the development and progression of prostate cancer (PCa), suggesting that Hh pathway inhibitors might be an effective strategy in the treatment of PCa. The combination of chemotherapeutic agents is one of the main approaches in cancer treatment, with the objective of improving efficacy. In the present study, we examined the effect of combing arsenic trioxide (ATO), a useful agent for Hedgehog-driven cancers, and cyclopamine (CYA), a classic Hh pathway inhibitor, on the suppression of PC3 cells (i.e., an androgen-independent PCa cell line). The combination of ATO and CYA more effectively inhibited the proliferation of PC3 cells than either single agent alone. In a xenograft mouse model, the combination of ATO and CYA significantly reduced tumor weight and volume in nude mice that were implanted with PC3 cells. The combination of ATO and CYA in PC3 cells resulted in a more distinct mode of Hh pathway inhibition and strengthened the S phase arrest. The present results indicate that a combination of ATO and CYA may be a rational strategy for treating PCa.

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“…Active DNA repair in normal cells will allow the cells to repair the damages and stay healthy, while active DNA repair in cancer cells will often result in repairing of chemotherapeutics induced DNA damage and induce chemoresistance. 53,54 Thus makes all the regulators of DNA repair mechanism including ROS, an important messenger for normal cell survival. Since the cells response to ROS varies based on cell type and magnitude of ROS formation, complete analysis of ROS in cells with different genetic background has to be analyzed in detail.…”

Section: Ros Induced Change In Dna Repairmentioning

confidence: 99%

Role of oxidative stress in facilitating carcinogenesis

Natarajan

2017

Int J Res Med Sci

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The carcinogenic role of ROS has been a great debate in the past and will be in the future. ROS is produced by both internal (inflammation) and external sources (UV). ROS is important for various important signalling mechanisms for the normal cellular survival. Even though literature exists to support the role of ROS in cancer, the magnitude of its expression and cell type it is expressed will determine whether it plays a positive (apoptosis) or negative role (genomic instability) in cancer. Apart from inducing DNA damage, ROS facilitates carcinogenesis by regulating cell cycle progression, gap junction, inflammation etc. The present review updates the recent discoveries of how ROS regulates these important cellular signalling mechanisms to facilitate carcinogenesis.

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Gli1 Protein Regulates the S-phase Checkpoint in Tumor Cells via Bid Protein, and Its Inhibition Sensitizes to DNA Topoisomerase 1 Inhibitors

Cited by 38 publications

References 70 publications

Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer

Rad6 upregulation promotes stem cell-like characteristics and platinum resistance in ovarian cancer

Synergism between arsenic trioxide and cyclopamine in the inhibition of PC3 cell survival via the Hedgehog signaling pathway

Role of oxidative stress in facilitating carcinogenesis

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