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<p>Homeodomain-interacting protein kinase 2 (HIPK2) can function either as a tumour suppressor or promoter in cancer. Understanding key features of HIPK2 context dependent effects in cancer could lead to novel therapeutic strategies. Our investigation of HIPK2 expression in gastric cancer (GC) showed it to be down regulated.HIPK2 manifested context dependent anti- and pro-tumorigenic effects as demonstrated in GC cell lines SNU638 and NUGC-3 (β-Catenin<sup>low</sup>, CD44<sup>Hi</sup>) and AGS (β-Catenin<sup>Hi</sup>, CD44<sup>low</sup>). The dualistic effects could be plausible due to HIPK2's differential impacts on the Akt-mTOR pathway. The HIPK2 inhibitor TBID further supported this context-dependent regulation of mTOR markers. Gene expression combined with protein–protein interactions analysis was used to identify the HIPK2-NLK-MAPK11 axis linked by their interaction with transcription factor MYB in GC. Validation of the axis was shown by increased&#xa0;NLK and MAPK11 expression in GC cell lines concordant with lower HIPK2 expression. Similarly, HIPK2 ectopically expressing cells showed lower levels of NLK and MAPK11 expression. Combinatorial targeting of HIPK2-NLK/MAPK11 axis with (HIPK2i + NLKi) or (HIPK2i + MAPK11i) resulted in a synergistic effect suppressing GC cell proliferation and mTOR markers. Targeting HIPK2 in combination with NLK or MAPK11 can be a promising strategy to overcome context dependent effects of HIPK2.</p>

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HIPK2 exhibits context dependent dualistic effects and combinatorial inhibition of HIPK2-NLK-MAPK11 axis manifests synergism against gastric cancer

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Aathithya Rangarajan,
  • Thirumoorthi Natarajan,
  • Sujatha Lakshminarayanan,
  • Shirley SunderSingh,
  • Jayavelu Subramani,
  • Priya Ramanathan,
  • Ramakrishnan Ayloor Seshadri,
  • Gopal Gopisetty

摘要

Homeodomain-interacting protein kinase 2 (HIPK2) can function either as a tumour suppressor or promoter in cancer. Understanding key features of HIPK2 context dependent effects in cancer could lead to novel therapeutic strategies. Our investigation of HIPK2 expression in gastric cancer (GC) showed it to be down regulated.HIPK2 manifested context dependent anti- and pro-tumorigenic effects as demonstrated in GC cell lines SNU638 and NUGC-3 (β-Cateninlow, CD44Hi) and AGS (β-CateninHi, CD44low). The dualistic effects could be plausible due to HIPK2's differential impacts on the Akt-mTOR pathway. The HIPK2 inhibitor TBID further supported this context-dependent regulation of mTOR markers. Gene expression combined with protein–protein interactions analysis was used to identify the HIPK2-NLK-MAPK11 axis linked by their interaction with transcription factor MYB in GC. Validation of the axis was shown by increased NLK and MAPK11 expression in GC cell lines concordant with lower HIPK2 expression. Similarly, HIPK2 ectopically expressing cells showed lower levels of NLK and MAPK11 expression. Combinatorial targeting of HIPK2-NLK/MAPK11 axis with (HIPK2i + NLKi) or (HIPK2i + MAPK11i) resulted in a synergistic effect suppressing GC cell proliferation and mTOR markers. Targeting HIPK2 in combination with NLK or MAPK11 can be a promising strategy to overcome context dependent effects of HIPK2.